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WO2025245500A1 - 2-(4-chloro-3-fluorophénoxy)-n-[trans-4-[5-[3-(trifluorométhoxy)-1-azétidinyl]-1,3,4-oxadiazol-2-yl]cyclohexyl]-acétamide destiné à être utilisé dans le traitement de la disparition de la substance blanche, de la maladie de huntington, du syndrome de charcot-marie-tooth, de la sclérose latérale amyotrophique ou pour augmenter l'activité du facteur d'échange de nucléotides de guanine - Google Patents

2-(4-chloro-3-fluorophénoxy)-n-[trans-4-[5-[3-(trifluorométhoxy)-1-azétidinyl]-1,3,4-oxadiazol-2-yl]cyclohexyl]-acétamide destiné à être utilisé dans le traitement de la disparition de la substance blanche, de la maladie de huntington, du syndrome de charcot-marie-tooth, de la sclérose latérale amyotrophique ou pour augmenter l'activité du facteur d'échange de nucléotides de guanine

Info

Publication number
WO2025245500A1
WO2025245500A1 PCT/US2025/030866 US2025030866W WO2025245500A1 WO 2025245500 A1 WO2025245500 A1 WO 2025245500A1 US 2025030866 W US2025030866 W US 2025030866W WO 2025245500 A1 WO2025245500 A1 WO 2025245500A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
subject
per day
isr
administering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/030866
Other languages
English (en)
Inventor
Sridhar NARAYAN
Mary MCMAHON
Steve LIANOGLOU
Paul August
Peng YUE
Bin Cao
Liyu ZHAO
Ye Tian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Zhongge Biological Technology Co Ltd
Revir Therapeutics Inc
Original Assignee
Shenzhen Zhongge Biological Technology Co Ltd
Revir Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Zhongge Biological Technology Co Ltd, Revir Therapeutics Inc filed Critical Shenzhen Zhongge Biological Technology Co Ltd
Publication of WO2025245500A1 publication Critical patent/WO2025245500A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • JRA Joint Research Agreement
  • Said one or more parties to the JRA consist of ReviR Therapeutics, Inc., and XTALPI INC. (including its affiliate Shenzhen Zhongge Biological Technology Co., Ltd.).
  • the claimed invention was made as a result of activities undertaken within the scope of said Joint Research Agreement.
  • the unfolded protein response comprises a set of signaling mechanisms that initiate relevant gene expression programs to restore protein homeostasis or promote neuronal death when chronic stress or stress overload is present. This function of the UPR has been proposed to play a key role in some neurodegenerative diseases.
  • the integrative stress response is an evolutionarily conserved intracellular signaling network that helps cells, tissues, and organisms adapt to variable environments and stay healthy.
  • the ISR responds to changes by reprogramming relevant gene expressions to restore homeostasis.
  • the formation of long-term memories requires the synthesis of new proteins, so inhibition of the ISR enhances long-term memory formation.
  • Activation of the ISR prevents this process, and age-associated cognitive deficits are often associated with ISR activation.
  • ISR activation occurs in a wide range of brain diseases. This activation process was confirmed by examining eIF2-P and PKR, PERK, and GCN2 phosphorylation in the brain, including from patient samples as well as samples from animal models of neurodegenerative diseases, e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’ s disease, traumatic brain injury, Down syndrome, and neurodegenerative disorders such as Charcot-Marie-Tooth disease.
  • ISR activation leads to cognitive deficits in mouse models of traumatic brain injury, aging, and neurodegenerative diseases.
  • eIF2B eukaryotic translation initiation factor 2B
  • eIF2B eukaryotic translation initiation factor 2B
  • GEF Guanine Nucleotide Exchange Factor
  • eIF2B eukaryotic translation initiation factor 2
  • GEF guanine nucleotide exchange factor
  • CMPD 1 potent eIF2B agonist COMPOUND 1
  • uses thereof for treatment of diseases associated with ISR such as neurodegenerative diseases (e.g., vanishing white matter (VWM), Huntington’s disease (HD), Charcot Marie Tooth syndrome (CMT) (including, for example CMT1 A, CMT1B, CMT2A or CMT2D), and Amyotropic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Chronic traumatic encephalopathy (CTE), and Aicardi-Goutieres Syndrome), for inhibition of integrated stress response (ISR), and/or for increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • VWM vanishing white matter
  • HD Huntington’s disease
  • CMT Charcot Marie Tooth syndrome
  • ALS Amyotropic Lateral Sclerosis
  • AD Alzheimer’s disease
  • PD Parkinson’s disease
  • CTE Chronic traumatic encephalopathy
  • GEF guanine nucleo
  • VWM vanishing white matter
  • a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of vanishing white matter (VWM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in treatment of vanishing white matter (VWM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a method of treating Huntington’s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • a use of a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof for treatment of Huntington’ s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in treatment of Huntington’s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • ALS Amyotropic Lateral Sclerosis
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • MEI 48415584v.l in some aspects, disclosed herein is a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of Amyotropic Lateral Sclerosis (ALS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof for use in treatment of Amyotropic Lateral Sclerosis (ALS) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has vanishing white matter (VWM)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide
  • MEI 48415584v.l exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject the composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the subject has vanishing white matter (VWM),
  • composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the subject has vanishing white matter (VWM)
  • VWM vanishing white matter
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Huntington’s disease (HD)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the
  • MEI 48415584v.l subject the composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the subject has Huntington’s disease (HD)
  • composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the subject has Huntington’s disease (HD)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Charcot Marie Tooth syndrome (CMT)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Charcot Marie Tooth syndrome (CMT)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Charcot Marie Tooth syndrome (CMT)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Amyotropic Lateral Sclerosis (ALS)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Amyotropic Lateral Sclerosis (ALS)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Amyotropic Lateral Sclerosis (ALS)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • CMT Charcot Marie Tooth syndrome
  • a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of Charcot Marie Tooth syndrome (CMT) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in treatment of Charcot Marie Tooth syndrome (CMT) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • the invention disclosed herein also provides methods, uses, and compositions of COMPOUND 1 for use in treating a number of other diseases as described herein below.
  • the CMT comprises I is CMT1A, CMT1B, CMT1C, CMT1D, IE, CMT1F, CMT1X, CMT2A, CMT2B, CMT2C, CMT2D, CMT2E, CMT2F, CMT2I, CMT2K, CMT2L, CMT2M, CMT2P, CMT2S, CMT2T, CMT4A, CMT4B1, CMT4B2, CMT4B3, CMT4C, CMT4D, CMT4E, CMT4F, CMT4G, CMT4AH, CMT4J, CMTX2, CMTX3, CMTX4, CMTX5, or CMTX6, or a combination thereof.
  • the CMT comprises / is CMT2A. In some embodiments, the CMT comprises I is CMT2D.
  • the compound (e.g., COMPOUND 1) or the pharmaceutical composition there of is administered orally, intravenously, or intragastrically.
  • the compound e.g., COMPOUND 1) or the pharmaceutical composition thereof is administered at a dose of about 0.1 mg/kg to 100 mg/kg e.g., about 0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12 mg/kg, 14 mg/kg, 16 mg/kg, 18 mg/kg, 20 mg/kg, 22 mg/kg, 24 mg/kg, 26 mg/kg, 28 mg/kg, 30 mg/kg, 40 mg/Kg, 50, mg/Kg, 60 mg/Kg, 70 mg/Kg, 75 mg/Kg, 80 mg/Kg, 90, mg/Kg, or 100 mg/Kg).
  • the compound e.g., COMPOUND 1
  • the pharmaceutically acceptable salt e.g., the compound or the pharmaceutically acceptable salt thereof
  • MEI 48415584v.l composition thereof is administered at a dose of about 3 mg/kg.
  • the compound (e.g., COMPOUND 1 ) or the pharmaceutical composition thereof is administered at a dose of about 30 mg/kg.
  • the compound e.g., COMPOUND 1) or the pharmaceutical composition thereof is administered at a dose of about 1 mg to 300 mg per day (e.g. , about Img per day, 5 mg per day, 10 mg per day, 15 mg per day, 20 mg per day, 25 mg per day, 30 mg per day, 35 mg per day, 40 mg per day, 45 mg per day, 50 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, 200 mg per day, 225 mg per day, 250 mg per day, 275 mg per day, or 300 mg per day) per patient.
  • about Img per day 5 mg per day, 10 mg per day, 15 mg per day, 20 mg per day, 25 mg per day, 30 mg per day, 35 mg per day, 40 mg per day, 45 mg per day, 50 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day
  • administering the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof results in increased nerve conduction velocity (NCV) (e.g., about 1.2 times, 1.5 times, 1.8 times, 2 times, 2.2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times higher than level before treatment).
  • NCV nerve conduction velocity
  • administering the compound (e.g., COMPOUND 1) or composition of any preceding aspects inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • the compound (e.g., COMPOUND 1) or composition thereof is administered orally and/or intravenously.
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound. In some embodiments, a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • FIGs. 1A and IB show dose response curves of COMPOUND 1 and reference compound (“Reference 1”) in inhibition of ATF4 expression as assessed by luciferase reporter assay.
  • FIGs. 2A-2C show dose response curves of COMPOUND 1 and Reference 1 (FIG. 2B) or Reference 2 (FIG. 2C) in inhibition of ATF4 expression as assessed by Western blot assay.
  • FIG. 3 shows a non-limiting illustration of generation of Eif2b5 R19IH/RI9IH mice.
  • FIG. 4 shows a non-limiting illustration of study design for assessing efficacy of COMPOUND 1 in mouse model of VWM.
  • FIGs. 5A-5C show body weight of Eif2b5 RI91H/RI9IH mice (also indicated as R191-H0 or HO mice) following treatment of the indicated doses of COMPOUND 1 , Reference 1 , or vehicle.
  • FIGs. 6A-6F show results of beam walking test to assess motor function. Time to cross the beam was measured (FIGS. 6A-6C) and the number of foot slips/falls was counted (FIGS. 6D-6F).
  • FIG. 7 shows the modulation of the integrated stress response (ISR) by Compound 1 and Reference 1 in the brains of Ez 27>5 R191H/R191H mice after treatment.
  • ISR integrated stress response
  • FIG. 8A shows the increased activation of the integrated stress response (ISR) in medium spiny neurons isolated from post-mortem brains of advanced (green) versus pre- symptomatic (grey) Huntington’s disease patients.
  • ISR integrated stress response
  • FIG. 8B shows the increased activation of the integrated stress response (ISR) in medium spiny neurons derived from induced pluripotent stem cells (iPSCs) from advanced (green) versus pre-symptomatic (grey) Huntington’s disease patients.
  • ISR integrated stress response
  • FIGs. 9A and 9B show the increase in expression of GDF15 and ATF4 (genes that are markers of ISR) in fibroblasts isolated from patients with Charcot-Marie-Tooth type 2A (CMT2A).
  • FIGs. 10A and 10B show body weight of mice after treatment.
  • FIGs. 11A-11C show grip strength of mice at 4- (FIG. 11 A), 6- (FIG. 1 IB), and 8 (FIG. 11b) weeks post treatment.
  • FIGs. 12A-12F show rotarod test of mice at 4- (FIGs. 12A and 12D), 6- (FIGs. 12B and 12E), and 8 weeks (FIGs. 12C and 12F) post treatment.
  • FIGs. 13A-13F show beam walk test of mice at 2- (FIG. 13A), 4- (FIG. 13B), 6-
  • FIGs. 14A- 14D show NCV test of mice at 2- (FIG. 14A), 4- (FIG. 14B), 6- (FIG. 14C), and 8 (FIG. 14D) weeks post treatment.
  • FIG. 15 shows PK results of mice treated with compound in chow.
  • FIG. 16 shows PK results of mice treated with Compound 1 through oral administration.
  • FIG. 17 shows representative transmission electron micrographs of the femoral nerve at 6000x and 15,000x magnification of wild-type and CMT2D Gur.s ,P278KY/+ mice after treatment.
  • FIG. 18 shows the integrated Stress Response (ISR) score in the spinal cord of CMT2D G’(//'.S7 P27SKY/+ and wild-type mice
  • Integrated Stress Response is an evolutionarily conserved signaling pathway that helps tissues adapt to stress and return to homeostasis.
  • eIF2B is the guanine nucleotide exchange factor that activates eIF2 (eukaryotic translation initiation factor 2) and promotes formation of the ternary complex that initiates mRNA translation in the absence of cellular stress.
  • eIF2B s substrate, eIF2, is composed of three subunits (a, p, y) and binds methionine initiator tRNA and guanosine triphosphate (GTP) to form the ternary complex required to initiate translation on AUG start codons.
  • GTP is hydrolyzed at the ribosome and eIF2-GDP is released, requiring reactivation by eIF2B to enable a new round of protein synthesis involving eIF2.
  • ISR In various stress conditions including ISR, however, eIF2 is phosphorylated by various stress-sensing kinases. ISR leads to the phosphorylation of eIF2, converting eIF2 from a substrate of eIF2B into a competitive inhibitor which reduces translation initiation events and decreases global protein synthesis.
  • ISR activation is a hallmark of several neurodegenerative disorders. Chronic ISR activation is observed in numerous neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), vanishing white matter disease (VWM), frontotemporal degeneration (FTD), and Charcot-Marie-Tooth syndrome type 2D (CMT2D), and Parkinson’s disease (PD).
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer’s disease
  • VWM vanishing white matter disease
  • FTD frontotemporal degeneration
  • CMT2D Charcot-Marie-Tooth syndrome type 2D
  • PD Parkinson’s disease
  • MEI 48415584v.l activators / agonists stabilize the decameric form of eIF2B.
  • eIF2B activators I agonists may enhance GEF activity of eIF2B by stabilizing the decameric form of the enzyme and increase thermostability of the eIF2B5 subunit.
  • eIF2B agonists can make cells insensitive to the effects of eIF2a-P by activating the GEF activity of eIF2B, thus allowing global protein synthesis to proceed with residual unphosphorylated eIF2a. This reverses I alleviates / eliminates the effects of eIF2a phosphorylation (e.g., by ISR), restoring translation in stressed cells, and blocking translation of ISR-activated mRNAs such as ATF4.
  • IS RIB a small molecule inhibitor of ISR initially identified in a phenotypic screen
  • ISR integrated stress response
  • eIF2B agonists have been found to increase long-term memory in mouse models. After 3 days of oral administration of the eIF2B activator ABBV-CLS-7262 (see Cho et al., Neurology 100(17supp2), 2023, doi.org/l 0.l212/WNL.00000000002038l), the brain function of the model animals could be restored to youthful levels.
  • eIF2B agonist Reference 1 (see Craig et al. , J. Med. Chem. 67(7):5758-5782, 2024) has been shown to reduce stress granules in ALS patient-derived iPSC-MNs, suggesting its utility in ALS treatment.
  • Reference 1 also restores body weight and motor function deficits in mice model of Vanishing white matter disease (VWM).
  • VWM Vanishing white matter disease
  • ISRIB was shown to provide protective effects against the A -mediated AD.
  • eIF2B agonists may inhibit some neurodegenerative diseases at a later stage and have the potential to treat diseases such as Alzheimer’s disease and Parkinson’s disease.
  • potent eIF2B activators/agonists e.g., COMPOUND 1
  • composition comprising said eIF2B activators/agonists, and uses thereof for treating or preventing diseases and disorders (e.g., neurodegenerative disease).
  • pharmaceutically acceptable carrier refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • an “effective amount” is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce one or more symptoms of a disease or condition).
  • An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • VWM vanishing white matter
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof:
  • a compound of the following formula or a pharmaceutically acceptable salt thereof for use in treatment of vanishing white matter (VWM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound (COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • a method of treating Huntington’s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof:
  • a use of a compound of the following formula or a pharmaceutically acceptable salt thereof for treatment of Huntington’ s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound (COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof for use in treatment of Huntington’s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • CMT Charcot Marie Tooth syndrome
  • a method of treating Charcot Marie Tooth syndrome (CMT) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof for use in treatment of Charcot Marie Tooth syndrome (CMT) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • the CMT comprises I is CMT1A, CMT1B, CMT1C, CMT1D, IE, CMT1F, CMT1X, CMT2A, CMT2B, CMT2C, CMT2D, CMT2E, CMT2F, CMT2I, CMT2K, CMT2L, CMT2M, CMT2P, CMT2S, CMT2T, CMT4A, CMT4B1, CMT4B2, CMT4B3, CMT4C, CMT4D, CMT4E, CMT4F, CMT4G, CMT4AH, CMT4J, CMTX2, CMTX3, CMTX4, CMTX5, or CMTX6, or a combination thereof.
  • the CMT comprises / is CMT2A. In some embodiments, the CMT comprises I is CMT2D.
  • the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof is administered orally, intravenously, or intragastrically.
  • the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof is administered at a dose of about 0.1 mg/kg to 100 mg/kg e.g., about 0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7
  • the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof is administered at a dose of about 3 mg/kg.
  • the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof is administered at a dose of about 30 mg/kg.
  • the compound (e.g. COMPOUND 1) or the pharmaceutical composition thereof is administered at a dose of about 1 mg to 300 mg per day (e.g., about Img per day, 5 mg per day, 10 mg per day, 15 mg per day, 20 mg per day, 25 mg per day, 30 mg per day, 35 mg per day, 40 mg per day, 45 mg per day, 50 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, 200 mg per day, 225 mg per day, 250 mg per day, 275 mg per day, or 300 mg per day, or about 1 mg to 10 mg per day, 1 mg to 30 mg per day, 1 mg to 100 mg per day, 5 mg to 25 mg per day, 5 mg to 50 mg per day, 5 mg to 100 mg per day, 5 mg to 150 mg per day, 5 mg to 200 mg per day, 10 mg to 50 mg per day, 10 mg to
  • administering the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof results in increased nerve conduction velocity (NCV) (e.g., about 1.2 times, 1.5 times, 1.8 times, 2 times, 2.2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times higher than level before treatment).
  • NCV nerve conduction velocity
  • administering the compound (e.g., COMPOUND 1) or the pharmaceutical composition thereof results in improvement of one or more of symptoms of CMT selected from the group consisting of muscle weakness, paralysis, muscle atrophy, decreased reflexes, hammertoes, foot drop, trips and falls, repeated ankle sprains, breathing problems, numbness or tingling, chronic pain, and loss or decrease in vision and hearing.
  • symptoms of CMT selected from the group consisting of muscle weakness, paralysis, muscle atrophy, decreased reflexes, hammertoes, foot drop, trips and falls, repeated ankle sprains, breathing problems, numbness or tingling, chronic pain, and loss or decrease in vision and hearing.
  • ALS Amyotropic Lateral Sclerosis
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of Amyotropic Lateral Sclerosis (ALS) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in treatment of Amyotropic Lateral Sclerosis (ALS) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof
  • eIF2B activators / agonists can enhance the GEF activity of eIF2B and ablate / alleviate the effect of ISR.
  • administering the compound or composition disclosed herein e.g., COMPOUND 1 inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR- associated biomarkers is reduced in the subject after administering the compound (e.g., COMPOUND 1).
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma- Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • VWM vanishing white matter
  • a method of treating vanishing white matter (VWM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (e.g., COMPOUND 1) or a pharmaceutically acceptable salt thereof
  • the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of vanishing white matter (VWM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof for use in treatment of vanishing white matter (VWM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about
  • MEI 48415584v.l 30% about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHACl in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • MEI 48415584v.l pharmaceutically acceptable carrier or excipient and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4).
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in treatment of Huntington’s disease (HD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or
  • ISR integrated stress response
  • MEI 48415584v.l increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a method of treating Charcot Marie Tooth syndrome (CMT) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula or a pharmaceutically acceptable salt thereof , wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%,
  • MEI 48415584v.l about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of Charcot Marie Tooth syndrome (CMT) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • MEI 48415584v.l in some aspects, disclosed herein is a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for use in treatment of Charcot Marie Tooth syndrome (CMT) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • ALS Amyotropic Lateral Sclerosis
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof
  • the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a use of a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof for treatment of Amyotropic Lateral Sclerosis (ALS) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a compound of the following formula (COMPOUND 1 ) or a pharmaceutically acceptable salt thereof for use in treatment of Amyotropic Lateral Sclerosis (ALS) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and the compound or a pharmaceutically acceptable salt thereof wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about
  • MEI 48415584v.l 30% about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has vanishing white matter (VWM) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the
  • MEI 48415584v.l composition comprising a compound of the following formula(COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has vanishing white matter (VWM), wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula(COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has vanishing white matter (VWM)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula(COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Huntington’s disease (HD) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • MEI 48415584v.l biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula(COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Huntington’s disease (HD) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Huntington’s disease (HD) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • MEI 48415584v.l subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Charcot Marie Tooth syndrome (CMT) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • CMT Charcot Marie Tooth syndrome
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Charcot Marie Tooth syndrome (CMT)
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • compositions comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Charcot Marie Tooth syndrome (CMT) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a method of inhibiting integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject comprising administering to the subject a composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Amyotropic Lateral Sclerosis (ALS) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ALS Amyotropic Lateral Sclerosis
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • ATF4 Activating Transcription Factor 4
  • CHAC1 ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1
  • TRIP3 Tribbles Pseudokinase 3
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Amyotropic Lateral Sclerosis (ALS) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR-associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR-associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof for use in inhibition of integrated stress response (ISR), or of increasing the guanine nucleotide exchange factor (GEF) activity of eIF-2B in a subject, comprising administering to the subject the composition comprising a compound of the following formula (COMPOUND 1) or a pharmaceutically acceptable salt thereof, wherein the subject has Amyotropic Lateral Sclerosis (ALS) wherein administering the compound inhibits integrated stress response (ISR) in the subject and/or increases the guanine nucleotide exchange factor (GEF) activity of eIF-2B.
  • ISR integrated stress response
  • GEF guanine nucleotide exchange factor
  • a level of one or more ISR- associated biomarkers is reduced in the subject after administering the compound.
  • the one or more ISR- associated biomarkers are selected from the group consisting of: Activating Transcription Factor 4 (ATF4), ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1), and Tribbles Pseudokinase 3 (TRIB3).
  • the ISR-associated biomarker is ATF4.
  • a level of ATF4 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of CHAC1 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • a level of TRIB3 in the subject is reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more compared to that prior to the treatment.
  • the compound (e.g., COMPOUND 1) or composition thereof is administered orally and/or intravenously.
  • ALS involves the death of motor neurons in the brain and spine and is related to protein homeostasis as well as cytoskeletal function.
  • eIF2B activators such as COMPOUND 1 , show efficacy in rescuing motor deficits in mice similar to ALS.
  • ISR is activated in ALS patients, and the TDP-43 stress granules have been found to accumulate in motor neurons.
  • eIF2B agonist helps to dissolve the TDP-43 stress granules, thus treating ALS.
  • eIF2B agonist also rescued mice from neurological deficits caused by persistent ISR in the brain / spinal cord.
  • the eIF2B agonist DNL343 penetrated the CNS and showed robust inhibition of the ISR pathway.
  • HD Huntington’s disease
  • HTT huntingtin
  • uORF upstream open reading frame
  • HTT uORF translation is reduced, leading to increased translation of HTT from the main ORF (similar mechanism as ATF4 translation upregulated by uORF during ISR) with increase in HTT protein levels.
  • a proline stretch after the HTT CAG repeat causes ribosomes to slow down and stall on the HTT mRNA. This activates stress and sequestering eIF5A which in turn leads to further ribosome stalling across the transcriptome.
  • Mutant huntingtin protein induces ER stress by interference of toxic oligomers with ER-associated degradation (ERAD) components.
  • mHTT induces PERK, ATF6, and IRE1 branch of the unfolded protein response in vitro. Phosphorylation of eIF2a increases due to expression of mHTT.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions disclosed herein are effective to treat, prevent HD and/or ameliorate the related symptoms, including, for example, movement disorders, trouble with cognitive skills, and/or brain cell damage and loss of brain tissue assessed by CT scan.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions disclosed herein can reduce eIF2a phosphorylation in HD patient.
  • AD Alzheimer’s Disease
  • AP P-amyloid
  • tau protein intracellular neurofibrillary tangles composed of tau protein.
  • the pathogenesis of this disease is associated with aberrant translational machinery through eIF2a.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions disclosed herein can prevent brain damaging, slow down and/or ameliorate brain damaging as assessed by magnetic resonance imaging (MRI), computerized tomography (CT), positron emission tomography (PET).
  • MRI magnetic resonance imaging
  • CT computerized tomography
  • PET positron emission tomography
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions disclosed herein can reduce and/or prevent increase of amyloid and/or tau protein in a biological sample (e.g. , cerebrospinal fluid) of AD patient, and/or prevent and/or ameliorate Amyloid P protein (A ) accumulation and accumulations of neurofibrillary tangles (NFTs), as assessed by imaging (MRI), computerized tomography (CT), positron emission tomography (PET), or histological staining.
  • MRI imaging
  • CT computerized tomography
  • PET positron emission tomography
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions disclosed herein can improve behavioral phenotypes in AD animal model, including, for example, improvement of platform crossing and prolonged target quadrant occupancy.
  • CMT Charcot-Marie-Tooth
  • the affected nerves slowly degenerate and lose the ability to communicate with their distant targets, resulting in muscle weakness and atrophy.
  • CMT Charcot-Marie-Tooth
  • tRNA synthetases are the largest gene family associated with CMT. These enzymes charge tRNAs with their cognate amino acid so the tRNA can participate in protein synthesis. Data from multiple mouse and cell-based models of aaRS-associated CMT show that the mutant aaRS sequesters tRNAs, causing ribosome stalling, and activation of the integrated stress response (ISR) in motor and sensory neurons through the activating kinase. Mutations in several tRNA synthetase genes have been identified in patients with CMTC, CMT2N and CMTB.
  • ISR integrated stress response
  • CMT type 1 is the most common subtype of CMT, accounting for roughly two-thirds of all cases. CMT1 is inherited in an autosomal dominant pattern.
  • CMT1A (caused by a duplication in the PMP22 gene on chromosome 17) accounts for around 70% to 80% of CMT1 cases, making it the most common subtype of CMT1.
  • This autosomal dominantly inherited demyelinating form of CMT is caused by a 1.5 Mb duplication on chromosome 17pl 1.2, containing the gene coding for peripheral myelin protein 22 (PMP22) and thus leading to three copies of the PMP22 gene.
  • Patients with CMT1A are usually slow runners in childhood, develop high arches and hammertoes and often require orthotics (braces) for ankle support. Varying degrees of hand weakness occur, often appearing as much as 10 years after foot and leg problems. Problems with balance because of ankle weakness and loss of proprioception (the brain’s ability to know where the limbs are in space) are common.
  • CMT1B is the second most common subtype of CMT1.
  • CMT1B is caused by a defect within the MPZ gene, which lies on chromosome 1.
  • the MPZ gene produces myelin protein
  • MEI 48415584v.l zero (MPZ protein), and the disruption of this mutated protein causes deficits within the myelin sheath.
  • People with early-onset CMT1B tend to have very slow nerve conduction velocities, with speeds ⁇ 15 m/s in the arms (normal >50 m/s).
  • a minority (7 %) of people with this diseasecausing variant in the MPZ gene have a childhood onset, with symptoms between 6 and 20 years of age. This group tends to have slow nerve conductions, between 15 and 25 m/s. The remainder of people with CMT1B have an adult onset, with symptoms tending to begin after age 40 and a comparatively milder presentation. Their nerve conduction studies tend to be in the intermediate range of between 35 and 45 m/s.
  • CMT1C is caused by disease-causing variants in the LITAF gene.
  • CMT1C affects fewer than 1% of people who have the disease.
  • Presentation is similar to CMT1A, with onset between the first and third decades, and weakness in the feet and hands, atrophy, and sensory loss and slow nerve conduction velocities (16-25 m/s).
  • CMT1D is caused by mutations in a gene on chromosome 10 called EGR2, which codes for the early growth response protein 2.
  • EGR2 codes for the early growth response protein 2.
  • CMT ID causes less than 1% of cases of CMT. Most people with CMT ID show severe symptoms in the first decade of life, including delayed motor milestones and nerve conduction velocities of 10 m/s or less (sometimes referred to as Dejerine Sottas syndrome). A few cases of CMT1D have milder symptoms that appear later in life. Other symptoms may include cranial nerve dysfunction and respiratory difficulties.
  • CMT IE Point mutations in the PMP22 gene cause CMT IE. People with CMT IE have earlier onset and more severe symptoms than those with CMT1 A. Children often present within the first two years of life with delayed walking. Conduction velocities in patients tend to be markedly reduced, usually under 10 m/s (normal in the arms is >50 m/s).
  • CMT IF is an autosomal dominant form of CMT in which the defect is on Chromosome 8 and mutations in gene NEFL that encodes the neurofilament light chain protein.
  • CMT2 represents 12% to 36% of all CMT cases.
  • CMT2 is characterized by distal
  • CMT2 can be caused by direct damage to nerve axons themselves. CMT2 is commonly referred to as “axonal” CMT.
  • CMT2A is the most common subtype of CMT2 (it accounts for 20% of the cases of axonal CMT) and is caused by defects in the MFN2 gene.
  • the MFN2 gene encodes for mitofusin 2, which is a protein involved in the fusion of cellular mitochondria.
  • MFN2 is a 757-amino acid long, nuclear encoded protein, anchored to the outer mitochondrial membrane by two transmembrane domains (TM1 and TM2).
  • CMT2B is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B.
  • CMT2B is characterized by severe ulceration problems and the defect IN in gene RAB7 located on chromosome 3.
  • CMT2B may be caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase.
  • CMT2C is an autosomal dominant neuropathy characterized by limb, diaphragm, and laryngeal muscle weakness.
  • Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.1 1 . All genes in this region were sequenced and heterozygous missense mutations were identified in the TRPV4 gene at positions C.805OT and c.806G>A, causing the amino acid substitutions R269C and R269H.
  • TRPV4 is a well known member of the TRP superfamily of cation channels. Onset is between infancy and the 6th decade.
  • CMT2D is caused by defects in the GARS gene, located on chromosome 7, which codes glycyl-tRNA synthetase.
  • the symptoms of CMT2D vary in patients, ranging from motor symptoms only to both sensory and motor symptoms.
  • CMT2E is caused by dominantly inherited mutations in the NEFL gene, located on chromosome 8, which codes for the neurofilament light chain protein. Neurofilaments form the structural framework determining the shape and size of nerve cells. Notably, mutations in NEFL protein also cause CMT IF. Onset is in the first to sixth decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and after years all patients have a pes cavus. Other signs may be present including hearing loss and postural tremor.
  • CMT2F is caused by dominant mutations in HSPB1 gene, located on chromosome 7, which codes for heat shock protein beta-1 (HSPB1). This protein helps neurofilaments maintain the diameter of axons. This is essential for the transmission of nerve impulses.
  • HSPB1 heat shock protein beta-1
  • CMT2I is caused by mutations in the myelin protein zero gene (MPZ), located on chromosome 1.
  • MPZ myelin protein zero gene
  • CMT2I is characterized by a late onset with with severe sensory loss associated with distal weakness mainly of the legs and absent or reduced deep tendon reflexeS. Mutations in MPZ also cause CMT1B.
  • CMT2K is Caused by mutations in the GDAP1 gene (8q 13.3), encoding a protein required for mitochondrial fission. About 25% of people with mutations in the GDAP1 gene have CMT2K.
  • GDAP1 codes for a protein called ganglioside-induced differentiation- associated protein 1 found in mitochondria. Onset occurs with a clinical picture including hypotonia, scoliosis, a hoarse voice, vocal cord paralysis and respiratory insufficiency. Nerve conduction velocities and pathological findings from sural nerve biopsies are indicative of a predominantly axonal neuropathy with some demyelinating features.
  • CMT2L is an autosomal dominant neuromuscular disorder characterized by muscle weakness and atrophy and sensory impairment of the distal lower and upper limbs resulting from a length-dependent axonal peripheral neuropathy. It is caused by mutations in the HSPB8 gene that encodes heat shock protein beta- 8.
  • CMT-GARS mutant models activate the ISR, specifically in alpha motor neurons and in a subset of sensory neurons. Gcn2 significantly alleviated neuropathy in CMT-GARS mice.
  • CMT1B mice e.g., PO glycoprotein mutation or MpzR98C/ + mice
  • CMT1A mice e.g., C3-PMP22 mice
  • ISR enhanced activation of ISR e.g., increased levels of P- eIF2a and/or total eIF2a
  • P0S63del is not detected in the myelin sheath, but is retained in the ER, where its accumulation triggers a canonical UPR, indicating a toxic gain of function.
  • Inactivation of Gadd34 restores motor function and rescues the neurophysiological and morphological deficits in S63del mice.
  • GCN2iB improves body weight and motor performance in CMT-Gars mice. Further, Gadd34 inhibition improves myelination in S63del DRG explant cultures and reduces demyelination in S63del mice.
  • the data herein also show increased expression of GDF15 and ATF4 (genes that are markers of ISR) in fibroblasts isolated from patients with CMT2A, indicating that inhibition of ISR can treat CMT2A.
  • the compounds (e.g. , COMPOUND 1) and/or the pharmaceutical compositions disclosed herein are effective to treat, prevent CMT and/or ameliorate the related symptoms, including, for example, weakness in legs, ankles and feet, high foot arches, curled toes, footdrop, and/or gait.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions disclosed herein can reduce eIF2a phosphorylation in CMT patient.
  • the CMT comprises /is CMT1 A, CMT1B, CMT1C, CMT1D, IE, CMT1F, CMT1X, CMT2A, CMT2B, CMT2C, CMT2D, CMT2E, CMT2F, CMT2I, CMT2K, CMT2L, CMT2M, CMT2P, CMT2S, CMT2T, CMT4A, CMT4B1, CMT4B2, CMT4B3, CMT4C, CMT4D, CMT4E, CMT4F, CMT4G, CMT4AH, CMT4J, CMTX2, CMTX3, CMTX4, CMTX5, or CMTX6, or a combination thereof.
  • the compounds (e.g., COMPOUND 1 ) and/or the pharmaceutical compositions thereof disclosed herein can reduce eIF2a phosphorylation in CMT1 A patient.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions thereof disclosed herein can reduce eIF2a phosphorylation in CMT2A patient.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions thereof disclosed herein can reduce eIF2a phosphorylation in CMT1B patient.
  • the compounds (e.g., COMPOUND 1) and/or the pharmaceutical compositions thereof disclosed herein can reduce eIF2a phosphorylation in CMT2D patient.
  • neurodegenerative disease e.g., neurodegenerative disease
  • diseases e.g., neurodegenerative disease
  • compounds e.g., COMPOUND 1
  • compositions of the present disclosure e.g., COMPOUND 1
  • the neurodegenerative disease includes but is not limited to: leukodystrophy, white matter lesions, dysmyelinating Disorders or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glial cell dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), Alexander’s disease, Alper’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Ataxia-telangiectasia, Batten disease (also called Spielmeyer- Vogt- Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler- Scheinker syndrome, Huntington’s disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (
  • MEI 48415584v.l type 8 spinocerebellar disorder spinal muscular atrophy, Steele-Richardson-Olszewski syndrome, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Krabbe disease, leukodystrophy due to mutations in the DARS2 gene (sometimes called leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), DARS2-associated spectrum disorders or Tabes dorsalis.
  • DARS2 gene sometimes called leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)
  • LBSL lactate elevation
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of cancer, including but are not limited to: human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer (including hepatocarcinoma), lymphoma (including B-acute lymphoblastic lymphoma, non- Hodgkin lymphoma) (e.g., Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin lymphoma, leukemia (including AML, ALL, and CML), and/or
  • cancer refers to: lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer or carcinoma.
  • leukemias include but are not limited to: acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, nonleukemic leukemia, nonleukocytosis leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoid leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of inflammatory diseases, which include but are not limited to: postoperative cognitive dysfunction, arthritis e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SUE), myasthenia gravis, juvenile onset diabetes, type 1 diabetes, Guillain- Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome, vasculitis, glomerulus nephritis, autoimmune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves’ ophthalmopathy, inflammatory bowel disease, Addison’s
  • arthritis
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of musculoskeletal diseases, which include but are not limited to: muscular dystrophy (e.g., Duchenne muscular dystrophy), Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, type-1 myotonic dystrophy or type-2 myotonic dystrophy, limb-girdle muscular dystrophy, multisystem proteinopathy, Rhizomelic chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata, Conradi-Hunermann syndrome, autosomal dominant punctate chondrodysplasia, stress-induced bone disease (e.g., stress-induced osteoporosis), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular dystrophy (
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of metabolic diseases, which include but are not limited to: non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes),
  • metabolic diseases include but are not limited to: non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes),
  • metabolic diseases include but are not limited to: non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of mitochondrial diseases, which include but are not limited to: Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kerns-Sell syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), mitochondrial DNA deletion syndrome (MDDS, such as Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, neuropathy, ataxia, and retinitis pigmentosa (NARP), Leber’s hereditary optic neuropathy (LHON) and Pearson syndrome.
  • mitochondrial diseases include but are not limited to: Barth syndrome, chronic progressive external ophthalmoplegia (cPEO),
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of hearing loss diseases, which include but are not limited to: mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-associated hearing loss, noise-induced hearing loss, hereditary hearing loss, hearing loss due to ototoxic exposure, disease, and trauma.
  • hearing loss diseases include but are not limited to: mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-associated hearing loss, noise-induced hearing loss, hereditary hearing loss, hearing loss due to ototoxic exposure, disease, and trauma.
  • the mitochondrial non-syndromic hearing loss and deafness is MT-RNR1 -associated hearing loss.
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of eye diseases, which include but are not limited to: cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-associated macular degeneration (AMD), or diabetic retinopathy.
  • eye diseases include but are not limited to: cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-associated macular degeneration (AMD), or diabetic retinopathy.
  • kidney diseases which include but are not limited to: Abderhalden-Kaufmann-Lignac syndrome (nephropathic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure/acute kidney injury, acute lobar nephropathy, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille Syndrome, Alport Syndrome, amyloidosis, ANCA vasculitis-associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa nephropathy, vasoconstrictor peptide antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, glomerulonep
  • MEI 48415584v.l nephropathy herbal medicine-associated nephropathy, Balkan endemic nephropathy, urinary tract arteriovenous malformations and fistulas, autosomal dominant hypocalcemia, Bardet- Biedl syndrome, Bartter syndrome, bath salt-induced acute kidney injury, Beer Potomania, beeturia, P-thalassemia nephropathy, bile cast nephropathy, autologous kidney BK polyomavirus nephropathy, bladder rupture, bladder sphincter dyssynergia, bladder tamponade, Border-Crossers’ nephropathy, Bourbon virus acute kidney Injury, burnt sugar cane harvesting and acute renal dysfunction, Byetta kidney failure, Clq nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, Callilepis Laureola poisoning,
  • MEI 48415584v.l disease uromodulin-associate nephropathy, type 1 adolescent hyperuricemic nephropathy, medullary sponge kidney, megaureterosis, meloxamine toxic-associated nephropathy, MELAS syndrome, membranous proliferative glomerulonephritis, membranous nephropathy, membranous glomerulopathy with occult IgGk deposition, Mesoamerican nephropathy, metabolic acidosis, metabolic alkalosis, methotrexate-associated renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change nephropathy, monoclonal gammopathy with renal significance, dysproteinemia, mouthwash toxicity, MUC1 nephropathy, polycystic dysplastic kidney, multiple myeloma, myeloproliferative neoplastic glomerulopathy, nail- patellar syndrome, NARP syndrome, n
  • MEI 48415584v.l Wegener s granulomatosis, granulomatosis with poly angiitis, West Nile Virus-associated chronic kidney disease, Wunderlich syndrome, Zellweger Syndrome or cerebral hepatorenal syndrome.
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of skin diseases, which include but are not limited to: acne, alopecia areata, basal cell carcinoma, Bowen’s disease, congenital erythropoietic porphyria, contact dermatitis, Darier’s disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), Paget’s disease of the breast, epidermolysis bullosa simplex, erythropoietic protoporphyrin, fungal infection of fingernails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, epileptic scars, keratosis pilaris, lichen
  • the methods, compounds e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of fibrotic diseases, which include but are not limited to: adhesive shoulder capsulitis, arterial stiffness, arthrofibrosis, atrial fibrosis, cardiac fibrosis and sclerosis, congenital liver fibrosis, Crohn’s disease, cystic fibrosis, Dupuytren’s contracture, endomyocardial fibrosis, colloid scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, scars, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, old myocardial infarction, Peyronie’s disease, pneumoconiosis, pneumonia, progressive massive fibrosis, pulmonary fibros
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of hemoglobin disorders, which include but are not limited to: dominant beta-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS/p thalassemia, HbE/p thalassemia, HbSC disease, pure alpha-i- thalassemia (phenotype of alphaO-thalassemia), hydrops fetalis with Hb Bart’s, sickle cell anemia, sickle
  • hemoglobin disorders include but are not limited to: dominant beta-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS/p thalassemia, HbE/p thalassemia, HbSC disease, pure alpha-i- thalass
  • MEI 48415584v.l cell traits sickle P-thalassemia, a-F-thalassemia, aO-thalassemia, alpha thalassemia associated with myelodysplastic syndromes, a-thalassemia with mental retardation syndrome (ATR), pO-thalassemia, P+-thalassemia, 5-thalassemia, y-thalassemia, P-thalassemia major, P- thalassemia intermedia, 5P-thalassemia and sySP-thalassemia.
  • ATR mental retardation syndrome
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of autoimmune diseases, which include but are not limited to: flaccid inability (achalasia), Addison’s disease, adult Still’ sdisease, agammaglobulinemia, pemphigus, amyloidosis, ankylosing Spondylitis, anti- GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmunehepatitis, autoimmune inner ear disease (ATED), autoimmune myocarditis, autoimmune ovarian inflammation, autoimmune pancreatitis, autoimmune retinitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor axonal neuropathy (AMAN), Balo Disease, leukodystrophy, benign mucocutaneous pemphigoid, herp
  • MEI 48415584v.l (MMN or MMNCB), multiple sclerosis, myasthenia gravis, myositis, episodic sleeping sickness, neonatal Lupus, optic neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis),, Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, type I polyglandular syndrome, type II polyglandular syndrome, type III polyglandular syndrome, wet polymyalgia, polymyositis, post-myocardial infarction syndrome
  • the methods, compounds (e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of viral infections, which include but are not limited to: influenza, human immunodeficiency virus (HIV), and herpes.
  • viral infections include but are not limited to: influenza, human immunodeficiency virus (HIV), and herpes.
  • the methods, compounds e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of malaria infections, which include but are not limited to: infections caused by plasmodium vivax, plasmodium ovale, plasmodium malariae and plasmodium falciparum.
  • the methods, compounds e.g., COMPOUND 1), and compositions of the present disclosure can be utilized for treatment of diseases with mutations that lead to induction of the unfolded protein response (UPR), which include but are not limited to: Marinesco-Sjogren syndrome., neuropathic pain, diabetic neuropathic pain, noise-induced hearing loss, non-syndromic sensory nerve hearing loss, age-related hearing loss, Wolfram syndrome, Darier White disease, Usher syndrome, collagen lesions, thin basal
  • URR unfolded protein response
  • the compounds (e.g., COMPOUND 1) and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming systems.
  • intermediate 6c (1g, 2.91 mmol) and CH2CI2 (30 mL), followed by N,N’ -carbonyldiimidazole (0.71 g, 4.37 mmol) under stirring conditions.
  • the reaction was completed after 16 hours at 25°C.
  • the reaction mixture was concentrated under reduced pressure to obtain a crude product.
  • Example 2 COMPOUND 1 shows superior potency in cellular models
  • MEI 48415584v.l This example demonstrates that the compound of the invention (e.g. , COMPOUND 1) is an activator I agonist for the GEF activity of e-IF2, in that it inhibits ATF4 translation (as measured by a luciferase reporter gene under the control of the ATF4 5’ UTR, in an ATF4 luciferase reporter plasmid) through activation of the eIF2.GTP.tRNAi Met ternary complex.
  • the ATF4 luciferase reporter plasmid is composed of two parts, the 5’ untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the 5’ untranslated region sequence of ATF4 containing two upstream open reading frames (uORFs) (NCBI database number BC022088.2) and the firefly luciferase coding gene are cloned into the pLVX-Puro vector (YouBio, VT1465).
  • the packaging plasmids for lentivirus are psPAX2 (YouBio, VT1444) and pMD2.G (YouBio, VT1443).
  • the above three plasmids are transfected simultaneously with X-tremeGENE 9 DNA transfection reagent in HEK293T/17 cells to create the HEK293T/17-ATF4 uORF-Luc-Puro monoclonal cell, and the lentivirus-containing culture medium is collected after 48 hours. Puromycin at 1 pg/mL is used to screen the virus-transduced HEK293T/17 cells, after which the monoclonal cells are obtained by limited dilution.
  • This cell line (HEK293T/17-ATF4 uORF-Luc-Puro) was utilized to detect the translational regulation of ATF4 and test the activity of eIF2B activator by cold fluorescence.
  • the experimental procedure was as follows: Spread 6000 HEK293T/17-ATF4uORF-Luc- Puro monoclonal cells in a 384- well plate to allow them to attach to the wall overnight. The test compound was dissolved in DMSO and then added to the cell culture solution together with 50 nM of toxic carotene. Incubate it for 6 hours. Toxic carotene acted to cause cellular stress and upregulate ATF4 protein translation. After 6 hours, cells were lysed using the One- Glo Luciferase Assay Kit (Promega #E6120), followed by reading the cold fluorescence values using the LUM program of the EnVision 2104 plate reader.
  • ATF4 reporter expression The relative expression of the ATF4 reporter gene (ATF4 reporter expression %) was calculated as follows:
  • ATF4 reporter expression % (ave_sample-ave_vc)/(ave_pc-ave_vc)*100%.
  • ave_vc average signal value of negative control
  • ave_pc average signal value of positive control
  • ave_sample average signal value of the sample
  • X-axis log value of compound concentration
  • Y-axis relative expression of ATF4 reporter gene
  • Top asymptote valuation on the curve
  • Bottom asymptote valuation under the curve
  • Hillslope slope of the fitted curve.
  • COMPOUND 1 has ECso less than 1 nM.
  • FIGs. 1A-1B show that COMPOUND 1 effectively inhibited the expression of ATF4 as assessed by luciferase reporter assay, with the ECso value about 2 pM, which was about 10,000 times lower than the ECso value of Reference 1 (about 23 nM).
  • COMPOUND 1 effectively inhibited ATF4 translation in a dose-dependent manner as assessed by Western blot analysis (FIGs. 2A-2C).
  • the ECso value of COMPOUND 1 was around 39 pM, which was about 333 times lower than the ECso value of a comparator compound Reference 1 (about 13 nM).
  • COMPOUND 1 can enhance/activate the activity of eIF2B, and can reduce the amount of ATF4 expression, which leads to the reduction of fluorescence intensity. This indicates that the present compounds can significantly alleviate the cellular stress caused by toxic carotene, reduce the integration stress response of the cell, and normalize the synthesis of intracellular proteins. Therefore, the present compound is an eIF2B agonist.
  • COMPOUND 1 has good in vitro liver microsomal stability, based on the livers microsomal stability assay performed according to the following procedure:
  • COMPOUND 1 has good cell membrane permeability, based on the assay performed according to the following procedure:
  • COMPOUND 1 Dilute COMPOUND 1 from 10 mM stock solution to a concentration of 10 pM in transport buffer (HBSS + BSA) and then apply it to the apical or 5 basolateral sides of the cell monolayer. Measure the permeability of COMPOUND 1 from the A to B direction or B to A direction in duplicate after 120 minutes of incubation at 37°C, 5% CO2 and 95% relative humidity. In addition, determine the exclusion ratio of COMPOUND 1 . Use the LC-MS/MS method to quantitatively analyze the test substance and reference substance based on the analyte/IS peak area ratio.
  • MEI 48415584v.l major P450 enzymes (CYP1 A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4) and has a low risk of drug-drug interactions.
  • the IC50 values of COMPOUND 1 for these five major P450 enzymes are greater than 10 pM, especially the IC50 values of CYP2D6 and CYP3A4 are both greater than 30 pM.
  • the assay was performed according to the following procedure:
  • phosphate buffer for liver microsomes Prepare phosphate buffer for liver microsomes. Add 169 pL of liver microsomes in phosphate buffer and 1 pL of working solutions of various concentrations of COMPOUND 1 or positive control compound to a 96-well plate. Place the culture plate in a water bath and preheat at 37°C for 15 minutes. After the incubation, add 10 pL of substrate to the culture plate (for CYP3A4-T, add 1 pL of substrate and 9 pL of K-Mg buffer to the culture plate), mix the incubation mixture on a rotary mixer for 10 seconds, and then add 20 pL of 10 mM NADPH solution to start the reaction at a final concentration of 1 mM. Repeat the experiment twice.
  • quench the reaction by adding 400 pL of quenching solution (cold ACN containing 500 nM toluene and 10 nM terfenadine). Centrifuge at 3220 g for 50 min at 4°C. Transfer 100 pL of supernatant to a new plate. Dilute the supernatant with 100 pL pure water. Mix well and analyze the sample using UPLC- MS/MS.
  • quenching solution cold ACN containing 500 nM toluene and 10 nM terfenadine.
  • COMPOUND 1 has excellent pharmacokinetic properties in mice, including but not limited to Cl (clearance rate), T1/2 (half-life), Cmax (peak concentration), AUC (drug concentration), area under the curve), F (bioavailability), etc.).
  • the PK evaluation was performed according to the following procedure:
  • MEI 48415584v.l Cocktail (4906845001, Roche), lyse cells on ice for 10 min, then centrifuge at 15,000 rpm at 4 °C for 10 min, collect supernatant as samples.
  • test compounds into the 12-well plate according to the plate map, staring from 1,000 or 100 nM, 3-fold serial dilution, 9 points, then add the Tg (final cone. 10 nM) into 12- well plate. Incubate cells at 37°C, 5% CO2 for 2 h.
  • VWM Vanishing White Matter
  • R191H-HO mice had body weight of around 21 g, significantly lower than the body weight of WT control mice (about 25 g) (FIG. 5 A).
  • the body weight of 1 mg/kg COMPOUND 1 -treated and 10 mg/kg COMPOUND 1 - treated R191H-HO mice quickly restored to around 24 g by 13 weeks of age, which was about 1 to 2 weeks post dosing. Weight gain of these groups of mice then slowed down and gradually increased to 25 g by 33-35 weeks of age, at which point WT mice had body weight of about 26 g.
  • COMPOUND 1 of the invention was far more potent than Reference 1 in suppresing ISR activity in the mouse model of VWM - Eif2b5 RI9IH/R,91H mice having homozygous R191H knock-in (R191H-HO mice) (see above in FIG. 3).
  • Vanishing White Matter is a chronic and progressive neurodegenerative disease that is driven by chronic activation of the integrated stress response (TSR) caused by recessive mutations in eIF2B.
  • TSR integrated stress response
  • COMPOUND 1 to agonize eIF2B and resolve the ISR
  • the Eif2b5 RI9IH/R19 mouse model for this disease was created by knocking in the R191H point mutation into both alleles of the Eif2b5 gene locus.
  • Such homozygous Knock-In (KI) “R191H-HO mice” were then treated with increasing doses of COMPOUND 1, or Reference 1, and the efficacy of compound treatment was measured via different modalities.
  • COMPOUND 1 treatment of the R191H-HO mice significantly reduced normalized ISR activity in a dose responsive manner. Similar dose-responsive results were also seen in
  • COMPOUND 1 is effective to reduce ISR activity in Huntington’s Disease, thus treating HD.
  • FIG. 8A shows increased activation of the integrated stress response (ISR) in medium spiny neurons isolated from post-mortem brains of advanced (right side) versus pre- symptomatic (left side) Huntington’s disease patients.
  • ISR integrated stress response
  • FANS Fluorescence-Activated Nuclear Sorting
  • ISR Activation Score in advanced patient’s brains were significantly higher than that in the brains of the pre- symptomatic HD patients. Both the striatonigral and striatopallidal medium spiny neurons from HD donors had increased activation of the ISR as compared to the normal donors. Thus, administering COMPOUND 1 to HD patients reduces ISR activity in the brains of the HD patients, thus treating HD.
  • FIG. 8B shows increased activation of the integrated stress response (ISR) in medium spiny neurons derived from induced pluripotent stem cells (iPSCs) from advanced (right side) versus pre-symptomatic (left side) Huntington’s disease patients.
  • ISR integrated stress response
  • iPSCs induced pluripotent stem cells
  • FIG. 8B shows increased activation of the integrated stress response (ISR) in medium spiny neurons derived from induced pluripotent stem cells (iPSCs) from advanced (right side) versus pre-symptomatic (left side) Huntington’s disease patients.
  • the ISR activation score was calculated from RNA
  • MEI 48415584v.l patients were significantly higher than that in iPSC derived from pre- symptomatic HD patients.
  • administering COMPOUND 1 to HD patients reduces ISR activity in the brains of the HD patients, thus treating HD.
  • COMPOUND 1 is efficacious to treat Char cot-Marie-Tooth type 2A (CMT2A)
  • COMPOUND 1 is effective to reduce ISR activity in Charcot-Marie-Tooth type 2A (CMT2A), thus treating CMT2A.
  • FIGs. 9A and 9B show the increase in expression of GDF15 and ATF4 (genes that are markers of ISR) in fibroblasts isolated from patients with Charcot-Marie-Tooth type 2A (CMT2A). It is apparent that ISR activity, as measured by expression of marker genes GDF15 and ATF4, was significantly higher in CMT2A patient fibroblasts. Thus, administering COMPOUND 1 to CMT2A patients reduces ISR activity in CMT2A patients, thus treating CMT2A.
  • GDF15 and ATF4 genes that are markers of ISR
  • Example 8 In vivo evaluation of efficacy of COMPOUND 1 on CMT2D mouse model.
  • NCV Nerve conduction velocity
  • Plasma from Groups 3 and 4 were collected on Day 4, Day 7, 2 weeks, 4 weeks, 6 weeks and 8 weeks post dosing for Compound 1 PK analysis. Samples were collected between 14:00 and 16:00 at each timepoint.
  • mice from G3 and G4 were switched to normal chow for 3 days at 10 weeks old (7 weeks of dosing) before PO dosing
  • Plasma sample collection 0.5, 1, 2, 4, 8 and 24h post dosing
  • mice were kept in individual ventilation cages at constant temperature and humidity with 3 mice in each cage.
  • Cages Made of polycarbonate. The size is 375 mm x 215 mm x 180 mm. The bedding material is com cob, which is changed twice per week.
  • Cage identification number of animals, sex, strain, date received, treatment, study number, group number and the date of the treatment.
  • Animal identification Animals were marked by ear coding.
  • Customized chow containing 2 concentrations of COMPOUND 1 , namely 30 and 300 mg/kg.
  • COMPOUND 1 was mixed into a measured amount of feed ingredients, followed by routine production and irradiation sterilization.
  • Stimulus Site Achilles tendon (AT) and sciatic notch (SN).
  • Two sterile acupuncture needles (diameter, 0.25mm) are inserted into AT, and then SN. They are stimulated with constant- voltage (20 v) square- wave pulses (duration, 0.1 ms; interval 3s, repeat 10 times), respectively.
  • M waves Compound muscle action potentials
  • H reflexes are recorded by another two acupuncture needles (diameter, 0.25mm) inserted into the interosseous muscle of hindpaw.
  • the firings are amplified and monitored using standard electrophysiological techniques and recorded onto a PC using CED Spike 2 software (Cambridge Electronics Design). An average of 10 recordings for each is used for measurements.
  • NCV (sciatic M wave latency - Achilles tendon M wave latency)/distance between SN and AT stimulation point
  • RNA later Collect Spinal cord (Thoracic and lumbar, RNA later, snap frozen), sciatic nerve (RNA later), femoral nerves (FFPE), Cervical spinal cord anterior horn (RNA later), Dorsal root ganglion (RNA later), TA (RNA later, snap frozen, FFPE), GA (RNA later, snap frozen, FFPE) from each mouse at predetermined time points post the treatment (as shown in Table 1).
  • the harvested plasmas were processed for pharmacokinetics analysis by LC/MS/MS
  • Femoral nerves were dissected and processed for transmission electron microscopy (TEM) analysis by fixating.
  • the motor and sensory branches of the femoral nerve were plastic-embedded, sectioned at 0.5 pm thickness, and stained with toluidine blue to visualize myelin.
  • Ultrathin sections were mounted on grids for TEM and imaged with a Transmission Electron Microscope. Samples examined for signs of pathology including abnormal, thin, or missing myelination, degenerating and/or regenerating axons, abnormalities in the axoplasm or cell bodies such as the presence of vacuoles, disrupted cytoskeletal components or organelles, with particular attention paid to abnormalities in mitochondria shape or localization. Axon number, nerve area, and diameter were measured and compared between genotypes and treatment.
  • Garsl encodes a tRNA synthetase that covalently links amino acids onto their cognate tRNAs. Mutations in GARS are associated with Charcot-Marie-Tooth neuropathies, type 2D (CMT2D). Gur.y P278KY/+ heterozygous mice have a severe axonal neuropathy of both sensory and motor axons. Specifically, mice have abnormal neuromuscular junction morphology and impaired transmission, reduced nerve conduction velocities, and a loss of large-diameter peripheral axons. On the C57BL/6 background, heterozygous mice fail to thrive and are always smaller than their littermates and develop muscle weakness and motor dysfunction like unsteady gait after weaning.
  • NCV Reduced nerve conduction velocity
  • Gar5 P278KY/+ heterozygous mice showed dramatically slower NCV (p ⁇ 0.05), indicating severe motor axon damage due to disease onset (FIGs. 14A-14D).
  • 300 mg/kg COMPOUND 1 in chow could significantly improve the NCV of Gur5 P278KY/+ heterozygous mice (p ⁇ 0.05).
  • Administration of 30 mg/kg COMPOUND 1 in chow also demonstrated beneficial effects on NCV improvement, although statistically significant differences were only observed at the 6-week post-treatment timepoint (potentially again could be attributable to limited sample size).
  • COMPOUND 1 concentrations of COMPOUND 1 in plasma samples are shown in FIGs. 16-17. Dose-dependent drug exposure was observed. Moreover, a stable drug concentration could be achieved with chow formulation of drug from 2 to 6 weeks. Since 30 and 300 mg/kg COMPOUND 1 in chow is equivalent to 3 and 30 mg/kg PO dose, the drug PK through single intragastric administration was investigated. COMPOUND 1 displayed time dependent elimination in plasma and peaked at Ih and 2h at the dosage of 3 mg/kg and 30 mg/kg respectively.
  • mice from each group was analyzed by RNAseq.
  • the ISR activity score was calculated for each sample by taking a weighted average of the expression of 88 genes previously reported to be direct targets of the ATF4 transcription factor as previously described [Labbe K, et al Nat. Commun. 15, 8301 (2024)]. Gene weights were determined by the loading of each gene on to the first principal component of the 88 gene expression matrix.
  • COMPOUND 1 was administered in chow to achieve the goal of maintaining relatively stable and sustained plasma drug concentrations while minimizing stress and injury to animals caused by frequent manual dosing. Both 30 mg/kg and 300 mg/kg COMPOUND 1 in chow resulted in increased body weight gain of Gar.y P278KY/+ heterozygous mice, and improved their performance in motor functional behavioral tests, including Beam walk (starting from 2 weeks post dosing) and Rotarod (only at 4 weeks post dosing), as well as muscle weakness reflected by grip strength test (starting from 4 weeks after dosing). Regarding NCV, 300 mg/kg COMPOUND 1 demonstrated more pronounced therapeutic improvements than 30 mg/kg.
  • COMPOUND 1 treatment led to an amelioration of the ISR score in spinal cord tissue of CMT2D G «r.y P278KY/+ mice, suggesting robust target and pathway engagement.

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Abstract

L'invention concerne un agoniste de eIF2B (par exemple, le COMPOSÉ 1) et ses utilisations pour le traitement de maladies, en particulier de maladies neurodégénératives, y compris la disparition de la substance blanche (VWM), la maladie de Huntington (HD), le syndrome de Charcot Marie Tooth (CMT) et la sclérose latérale amyotrophique (ALS).
PCT/US2025/030866 2024-05-23 2025-05-23 2-(4-chloro-3-fluorophénoxy)-n-[trans-4-[5-[3-(trifluorométhoxy)-1-azétidinyl]-1,3,4-oxadiazol-2-yl]cyclohexyl]-acétamide destiné à être utilisé dans le traitement de la disparition de la substance blanche, de la maladie de huntington, du syndrome de charcot-marie-tooth, de la sclérose latérale amyotrophique ou pour augmenter l'activité du facteur d'échange de nucléotides de guanine Pending WO2025245500A1 (fr)

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Citations (3)

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