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WO2025151669A1 - Inhibition de clk2 en tant que contre-mesure de rayonnement - Google Patents

Inhibition de clk2 en tant que contre-mesure de rayonnement

Info

Publication number
WO2025151669A1
WO2025151669A1 PCT/US2025/010986 US2025010986W WO2025151669A1 WO 2025151669 A1 WO2025151669 A1 WO 2025151669A1 US 2025010986 W US2025010986 W US 2025010986W WO 2025151669 A1 WO2025151669 A1 WO 2025151669A1
Authority
WO
WIPO (PCT)
Prior art keywords
radiation
clk2
inhibitor
subject
cells
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/US2025/010986
Other languages
English (en)
Inventor
Ryan Raj POSEY
David B. CHOU
Donald E. Ingber
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.)
Harvard University
Original Assignee
Harvard University
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 Harvard University filed Critical Harvard University
Publication of WO2025151669A1 publication Critical patent/WO2025151669A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • aspects of the present disclosure relate to a method, comprising administering a CLK2 inhibitor to a subject who has been or will be exposed to radiation.
  • the subject has been exposed to radiation therapy.
  • the subject is exposed to radiation before administration of the CLK2 inhibitor, during administration of the CLK2 inhibitor, after administration of the CLK2 inhibitor, or combinations thereof.
  • Figures 4A-4F Multi-organ Chip Assessment of CLK2 inhibition as a therapeutic strategy.
  • Figure 4A Schematic showing experimental overview.
  • Figure 4B Cell counts from the vascular channel (left), apical (epithelial) channel (center), and villus height measurements (right) of intestine chips treated as indicated.
  • Figure 4C Cytokine levels measured by Luminex assay.
  • Figure 4D VE-Cadherin average quantification per chip (left) and representative images (right) of lung chips treated as indicated.
  • Figure 4E Quantification per chip (left) and representative images (right) of PBMC adhesion to lung chips (right).
  • Figure 4F Levels of cytokines detected by Luminex assay.
  • a CLK2 inhibitor inhibits (i.e., reduce or eliminate) CLK2 protein activity (e.g., serine, threonine, or tyrosine phosphorylation).
  • a CLK2 inhibitor may inhibit CLK2 protein activity (e.g., serine, threonine, or tyrosine phosphorylation) by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%, relative to a control, for example, a baseline level of CLK2 protein expression.
  • the CLK2 inhibitor is Cirtuvivint. In some embodiments, the CLK2 inhibitor is Lorecivivint. In some embodiments, the CLK2 inhibitor is TG003. In some embodiments, the CLK2 inhibitor is Silmitasertib.
  • the CLK2 inhibitor is TG003:
  • the CLK2 inhibitor is Lorecivivint:
  • the CLK2 inhibitor is SM08502:
  • the CLK2 inhibitor is SM04755: In some embodiments, the CLK2 inhibitor is Cpd-2:
  • the CLK2 inhibitor is T3:
  • the CLK2 inhibitor is CC-671:
  • the CLK2 inhibitor is T-025:
  • I e CLK2 inhibitor is NR9:
  • the CLK2 inhibitor is DB18: , the CLK2 inhibitor is ML106: In some embodiments, the CLK2 inhibitor is MU1210:
  • the CLK2 inhibitor is KuWall51: In some embodiments, the CLK2 inhibitor is CX-4945: In some embodiments, the CLK2 inhibitor is acrifoline:
  • the CLK2 inhibitor is ML315:
  • the CLK2 inhibitor is an indazole derivative, imidazopyridine derivative, a benzothiazoline derivative, a pyrrolopyrimidine derivative, a purine derivative, a pyrazolopyridazine derivative, a quinoline derivative, a quinazoline derivative, a furopyridine derivative, a dihydropyrroloindol-one derivative, a benzonaphthyridine derivative, or a benzofluorene derivative.
  • a derivative is produced by converting a chemical compound into a product (the reaction's derivate/derivative) of similar chemical structure.
  • Other small molecule CLK2 inhibitors are contemplated.
  • the CLK2 inhibitor is an antibody or antigen-binding fragment thereof.
  • antibody refers to a molecule that specifically binds to, or is immunologically reactive with, a particular antigen and includes at least the variable domain of a heavy chain, and normally includes at least the variable domains of a heavy chain and of a light chain of an immunoglobulin. Unless otherwise indicated, the term “antibody” (Ab) is meant to include both intact (whole) molecules as well as antibody fragments (such as, for example, Fab and F(ab’)2 fragments) that are capable of specifically binding to a target protein.
  • Antibodies include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, heteroconjugate antibodies (e.g., bi-, tri-, and quad-specific antibodies, diabodies, triabodies, and tetrabodies), single-domain antibodies (sdAb), epitope-binding fragments, e.g., Fab, Fab’, and F(ab’)2, Fd, Fvs, single-chain Fvs (scFv), rlgG, single-chain antibodies, disulfide- linnked Fvs (sdFv), fragments containing either a Vi.or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies.
  • heteroconjugate antibodies e.g., bi-, tri-, and quad-specific antibodies, diabodies, triabodies, and tetrabodies
  • single-domain antibodies sd
  • Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2) or subclass of immunoglobulin molecule.
  • antigen-binding fragment refers to one or more fragments of an immunoglobulin that retain the ability to specifically bind to a target antigen.
  • the antigen-binding function of an immunoglobulin can be performed by fragments of a full- length antibody.
  • the antibody fragments can be a Fab, F(ab’)2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody.
  • binding fragments encompassed by the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab’)2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb including VH and VL domains; (vi) a dAb fragment that consists of a VH domain; (vii) a dAb that consists of a VH or a VL domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be joined by a synthetic link
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)).
  • scFv single chain Fv
  • Other antibody fragments are described above. These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies.
  • Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in certain cases, by chemical peptide synthesis procedures known in the art.
  • the CLK2 inhibitor is a nucleic acid. In some embodiments, the CLK2 inhibitor is an antisense oligonucleotide. Antisense oligonucleotides (ASOs) are small- sized single- stranded nucleic acids that bind to their target RNA or DNA sequence inside cells to cause gene silencing. In some embodiments, the CLK2 inhibitor is an ASO that binds to a nucleic acid encoding CLK2.
  • ASOs Antisense oligonucleotides
  • the CLK2 inhibitor is an RNA interference molecule.
  • RNA interference molecules include micro RNAs, short interfering RNAs, and short hairpin RNAs.
  • a CLK2 inhibitor is an RNA interference molecule that binds to a nucleic acid encoding CLK2.
  • the CLK2 inhibitor is a programmable nuclease, for example, an RNA-guided nuclease.
  • programmable nucleases include CRISPR nucleases, zinc finger nucleases, transcription activator- like effector nucleases, and meganucleases.
  • Transcription activator-like effector nucleases are restriction enzymes that can be engineered to cut specific sequences of DNA. They are made by fusing a TAL effector DNA-binding domain to a DNA cleavage domain (a nuclease which cuts DNA strands). Transcription activator-like effectors (TALEs) can be engineered to bind to practically any desired DNA sequence, so when combined with a nuclease, DNA can be cut at specific locations.
  • TALEs Transcription activator-like effectors
  • the restriction enzymes can be introduced into cells, for use in gene editing or for genome editing in situ, a technique known as genome editing with engineered nucleases.
  • Zinc-finger nucleases are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger domains can be engineered to target specific desired DNA sequences, and this enables zinc-finger nucleases to target unique sequences within complex genomes. By taking advantage of endogenous DNA repair machinery, these reagents can be used to precisely alter the genomes of higher organisms.
  • the CRISPR-Cas system is a prokaryotic immune system that confers resistance to foreign genetic elements such as those present within plasmids and phages and provides a form of acquired immunity.
  • RNA harboring the spacer sequence helps Cas (CRISPR- associated) proteins recognize and cut foreign pathogenic DNA.
  • Other RNA-guided Cas proteins cut foreign RNA.
  • CRISPR are found in approximately 50% of sequenced bacterial genomes and nearly 90% of sequenced archaea. These systems have created CRISPR gene editing that commonly utilizes the cas9 gene.
  • an effective amount of a CLK2 inhibitor reduces radiation toxicity by at least 20%, at least 30%, at least 40%, or at least 50%, relative to a control or baseline. In some embodiments, a reduction in radiation toxicity is assessed by evaluating endothelial cell numbers. Thus, in some embodiments, an effective amount of a CLK2 inhibitor increases endothelial cell number in a subject relative to a control or baseline. An increase in endothelial cell number may be, for example, an increase by at least 20%, at least 30%, at least 40%, or at least 50%, relative to a control or baseline. In some embodiments, a reduction in radiation toxicity is assessed by evaluating endothelial cell death.
  • an effective amount of a CLK2 inhibitor decreases endothelial cell death in a subject relative to a control or baseline.
  • a decrease in endothelial cell death may be, for example, a decrease by at least 20%, at least 30%, at least 40%, or at least 50%, relative to a control or baseline.
  • cell death such as endothelial cell apoptosis
  • cell death may be decreased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, relative to a baseline or control.
  • any of the agents disclosed herein may be administered to a subject (e.g., mammalian subject, such as a human, mouse, rabbit, goat, sheep, pig, or non-human primate) to treat exposure to radiation.
  • a subject e.g., mammalian subject, such as a human, mouse, rabbit, goat, sheep, pig, or non-human primate
  • treating refers to the application or administration of a CLK2 inhibitor to a subject, who has been exposed to radiation, is at risk of exposure to radiation, or has a condition or disease arising from radiation exposure, with the purpose to cure or improve the condition or disease.
  • a CLK2 inhibitor is administered as a treatment to a subject after exposure to radiation.
  • a CLK2 inhibitor may be administered to a subject as a treatment within about 12 hours, about 24 hours, about 36 hours, or about 48 hours.
  • a CLK2 inhibitor is administered without about a week or about a month after exposure to radiation.
  • a subject is considered “at risk of exposure” to radiation, for example, if the subject plans to undergo a medical procedure involving radiation therapy, works or regularly spends time within the vicinity of a source of radiation, or plans to travel to region within the vicinity of a source of radiation.
  • Professionals at risk of radiation exposure include, for example, healthcare professionals (e.g., radiologists and radiologic technologists, nuclear medicine technologists, and radiation therapists), nuclear power plant workers (e.g., engineers and technicians), research scientists (e.g., biologists and medical researchers, aviation industry professionals (e.g., airline pilots and cabin crew), military personnel (e.g., nuclease submarine crew and radiologic technicians), mining and industrial workers (e.g., uranium miner and industrial radiographers), and emergency response teams (e.g., hazmat teams and firefighters).
  • healthcare professionals e.g., radiologists and radiologic technologists, nuclear medicine technologists, and radiation therapists
  • nuclear power plant workers e.g., engineers and technicians
  • research scientists e.g., biologists and medical researchers
  • aviation industry professionals e.g., airline pilots and cabin crew
  • military personnel e.g., nuclease submarine crew and radiologic technicians
  • mining and industrial workers e.g., uran
  • Ionizing radiation has enough energy to remove tightly bound electrons from atoms, creating ions in the process. This type of radiation poses a significant risk to living tissues.
  • ionization radiation include alpha particles, beta particles, gamma rays, x-rays, and neutron radiation.
  • Non-ionizing radiation has less energy and cannot remove electrons from atoms. Although generally considered less harmful, excessive exposure to certain types of non-ionizing radiation can still pose risks.
  • non-ionizing radiation include radio waves, microwaves, infrared radiation, visible light, ultraviolet radiation, and extremely low frequency (ELF) radiation.
  • HSIMEC lentiviruses containing LCv2-GL with an sgRNA against TP53 (data not shown).
  • TIDE Tracking of Indels by Decomposition

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Toxicology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La divulgation concerne des méthodes d'utilisation d'inhibiteurs de CLK2 dans le traitement de sujets exposés à un rayonnement.
PCT/US2025/010986 2024-01-10 2025-01-09 Inhibition de clk2 en tant que contre-mesure de rayonnement Pending WO2025151669A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463619361P 2024-01-10 2024-01-10
US63/619,361 2024-01-10

Publications (1)

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WO2025151669A1 true WO2025151669A1 (fr) 2025-07-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140342993A1 (en) * 2007-01-10 2014-11-20 Purdue Research Foundation Kinase inhibitors and uses thereof
US20200338074A1 (en) * 2015-06-12 2020-10-29 Dana-Farber Cancer Institute, Inc. Combination therapy of transcription inhibitors and kinase inhibitors
US20220062240A1 (en) * 2018-06-26 2022-03-03 Biosplice Therapeutics, Inc. Methods of treating cancer using a clk inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140342993A1 (en) * 2007-01-10 2014-11-20 Purdue Research Foundation Kinase inhibitors and uses thereof
US20200338074A1 (en) * 2015-06-12 2020-10-29 Dana-Farber Cancer Institute, Inc. Combination therapy of transcription inhibitors and kinase inhibitors
US20220062240A1 (en) * 2018-06-26 2022-03-03 Biosplice Therapeutics, Inc. Methods of treating cancer using a clk inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOSHIDA ET AL.: "CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer", CANCER RES, vol. 75, no. 7, 31 March 2015 (2015-03-31), pages 1516 - 1526, XP009535858, Retrieved from the Internet <URL:https://doi.org/10.1158/0008-5472.CAN-14-2443> DOI: 10.1158/0008-5472.CAN-14-2443 *

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