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WO2022237922A1 - Composés antitumoraux à base d'hétérocycles d'azote et leur utilisation en tant que médicaments - Google Patents

Composés antitumoraux à base d'hétérocycles d'azote et leur utilisation en tant que médicaments Download PDF

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Publication number
WO2022237922A1
WO2022237922A1 PCT/CZ2022/050002 CZ2022050002W WO2022237922A1 WO 2022237922 A1 WO2022237922 A1 WO 2022237922A1 CZ 2022050002 W CZ2022050002 W CZ 2022050002W WO 2022237922 A1 WO2022237922 A1 WO 2022237922A1
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Prior art keywords
phenyl
pyrrolo
mmol
sulfonyl
pyridine
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Ceased
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English (en)
Inventor
Lukas GORECKI
Martina REZACOVA
Jan KORABECNY
Darina MUTHNA
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Fakultni Nemocnice Hradec Kralove
Univerzita Karlova Lekarska Fakulta V Hradci Kralove
Original Assignee
Fakultni Nemocnice Hradec Kralove
Univerzita Karlova Lekarska Fakulta V Hradci Kralove
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Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to novel derivatives of nitrogen heterocyclic compounds, use thereof as medicaments, and to pharmaceutical preparations containing these compounds.
  • Tumor resistance to treatment is a serious problem.
  • One of the key causes of resistance is the natural ability of all cells to repair their DNA.
  • DNA repairs are indispensable for cellular life and development, but they reduce the effect of treatment during radiation and chemotherapy because they repair DNA lesions caused by the treatment.
  • cellular DNA damage response has become a field of study in cancer research.
  • DNA damage response contains complex, and not yet completely described, signaling cascades with a hundred different proteins. Minor interventions in these signaling pathways by means of drugs may contribute to increasing the efficacy of cytotoxic therapy.
  • PIKK phosphatidylinositol 3 -kinase-related kinase
  • ATM ataxia telangiectasia mutated
  • ATR ataxia telangiectasia and Rad3 -related
  • DNA-PK DNA-dependent protein kinase
  • the ATR kinase is activated in response to replication stress which can be caused by a variety of endogenous and exogenous factors. In the event of replication stress, the replication fork stops and stabilizes. Inhibition of the ATR kinase results in a replication fork collapse leading to irreversible and potentially lethal DNA damage. If this damage is not resolved quickly, apoptosis can be triggered [[SALDIVAR, Joshua C., David CORTEZ and Karlene A. CIMPRICH. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nature reviews. Molecular cell biology [online] 2017, 18(10), 622-636.
  • ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy. Pharmacology & Therapeutics [online]. 2020, 107518. ISSN 1879-016X. Available from: doi: 10.1016/j.pharmthera.2020.107518; GORECKI, Lukas, Martin ANDRS and Jan KORABECNY. Clinical Candidates Targeting the ATR-CHK1-WEE1 Axis in Cancer. Cancers [online]. 2021, 13(4), 795. Available from: doi: 10.3390/cancersl3040795] These compounds can be used in the treatment of cancer both in monotherapy and in combination with standard chemo- or radiotherapeutics.
  • the present invention provides nitrogen heterocyclic compounds of general formula I wherein X is C or N;
  • R 1 is selected from C1-C6 alkyls
  • Z- is -CH 2 - or -C(O)-;
  • R 2 is a primary or secondary amine bound via Z to the heterocyclic core, and selected from the group comprising anilino; anilino substituted by di(Cl-C6 alkyl)amino group in position 2, 3, or 4; benzylamino; benzylamino substituted by di(Cl-C6 alkyl)amino group in position 2, 3, or 4; 4- phenylpiperidin-l-yl, 1-(C1-C6 alkyl)piperazin-4-yl, 1,2,3,4-tetrahydroisoquinolinyl; 1-(C1-C6 alkanesulfonyl)piperazin-4-yl; 4-[4-(Cl-C6 alkyl)-piperazin-l-yl]piperidin-l-yl; and pharmaceutically acceptable salts thereof with alkali metals, or addition salts thereof with acids.
  • Addition salts with acids include in particular hydrochlorides, hydrobromides, hydrofluorides, hydroiodides, nitrates, nitrites, sulphates, bisulphates, borates, citrates, fumarates, lactates, malates, maleates, mesylates, tosylates, oxalates, tartrates, acetates, formates, salicylates, aspartates, adipates, benzoates, palmitates, stearates, besylates, phosphates, carbonates, hydrogencarbonates.
  • X is N and Z is -C(O)-.
  • C1-C6 alkyl is a saturated hydrocarbon residue, which may be linear, branched or cyclic.
  • a branch or cyclic alkyl can exist for the C3-C6 alkyls.
  • alkyl may be selected from the group comprising methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the alkyls may be the same or different.
  • the present invention provides novel derivatives of nitrogen heterocyclic compounds, in particular 1 H-pyrrolo
  • These compounds consist of three fundamental fragments that are necessary for proper ligand orientation in the ATP -binding cavity of the ATR kinase.
  • the first fragment is a nitrogen heterocycle with a putative p-p interaction in the kinase cavity.
  • the nitrogen heterocycle is a disubstituted lH-pyrrolo
  • a bulky alkane sulfonylphenyl substituent is attached via a C-C bond at position 5.
  • This substituent is necessary to maintain the selectivity for ATR kinase.
  • This substituent also serves as a hydrogen bond donor to ensure the affinity for the enzyme.
  • the other side of the molecule is preferably represented by basic substituents.
  • the basic substituents provide for a higher binding to the enzyme cavity, especially through interactions with the anionic region of the protein.
  • These basic mindfulheads“ are attached to the nitrogen heterocycle at position 2 or 3 for 1 H- pyrrolo[2,3-b]pyridine and at position 3 for 1 H-pyrazolo
  • the methylene linker lies in the flexibility of the substituent with the presumed suitable orientation of the ligand into the anionic pocket.
  • the carbonyl linker can provide additional hydrogen bonds for the fixation of the molecule (rigid carbonyl character), whereby the kinase selectivity can be achieved in the overall proper construction of the compounds. Both of these approaches have proven to be effective.
  • the compounds of the present invention are preferably selected from the group:
  • the present invention further provides the nitrogen heterocyclic compounds of general formula I for use as medicaments, more specifically for use in the treatment of tumour diseases.
  • the compounds of general formula I are suitable for medical use in monotherapy or in combination therapy together with further antitumour medicaments (e.g., anthracyclin orplatinum cytostatics) and/or in combination with radiotherapy.
  • Use in monotherapy involves the administration of the medicament of general formula I to stop the progression of the tumour growth and development, or to reduce the number of tumour cells.
  • Use in combination therapy involves the administration of the medicament of general formula I in combination with standard radiotherapy or with standard chemotherapy, to potentiate the effect of the standard therapy against the tumour cells.
  • treatment refers to the administration of a medicament with the aim of reducing the symptoms of a disease. This effect may be related to slowing the progression of the disease, or improving the patient's health in any way. This includes reducing or stopping tumour cell proliferation, preventing or suppressing invasion and metastasis, promoting genomic instability and mutagenicity, preventing resistance to cell death, avoiding replication immortality, or promoting tumour suppressors.
  • the invention further provides a pharmaceutical composition comprising at least one nitrogen heterocyclic compound of formula I according to the invention and at least one pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients may include carriers, fillers, binders, solvents, and the like, as known to those skilled in the art of pharmaceutical formulation.
  • the compounds of the invention may in particular be administered orally or parenterally.
  • the pharmaceutical composition can be formulated into various pharmaceutical formulations, such as granules, powders, tablets, gels, capsules, syrups, emulsions, suspensions and forms for parenteral administration such as injectable formulations, infusion formulations, sprays or suppositories. These formulations can be prepared by generally known methods.
  • a pharmaceutical formulation for injection can be obtained, for example, by the following procedure.
  • the active ingredient is dissolved, suspended or emulsified in an aqueous medium, for example water, saline or Ringer's solution, or in an oily medium (e.g.
  • a dispersing ingredient e.g. Tween ® 80, HCO ® 60, polyethylene glycol, carboxymethylcellulose or sodium alginate
  • a preservative e.g. methyl p-hydroxybenzoate. propyl p-hydroxybenzoate. benzyl alcohol, chlorobutanol or phenol
  • an isotonic agent e.g. sodium chloride, glycerol, sorbitol or glucose
  • solubilizers e.g. sodium salicylate, sodium acetate
  • stabilizers e.g. human serum albumin
  • Nitrogen heterocyclic compounds of formula I derived from 1 H-pyrrolo[2,3-b]pyridinc. wherein the secondary amine in position 3 of the ring is attached by a methylene linker, can be prepared according to Scheme 1.
  • reductive amination is performed using sodium triacetoxyborohydride.
  • an aromatic aldehyde 21 is reacted with a secondary amine to give an iminium intermediate, which is immediately reduced to a tertiary amine (compounds 22-24).
  • a modified Suzuki-Miyaura Cross-Coupling is performed, using a microwave reactor.
  • 2.3-b Ipyridinc or 1 H- pyrazolo[3,4-b]pyridine, wherein a primary or secondary amine is attached via a carbonyl linker in position 2 or 3 of the ring, can be prepared according to the procedure shown in Scheme 2 (25-27).
  • a modified Suzuki-Miyaura Cross-Coupling catalyzed by Pd(dppf)Cl 2 .DCM is performed.
  • this reaction is performed under standard conditions with heating at 110 °C for three days.
  • esters In the case of products 32-35, the ester is directly hydrolyzed and the resulting products are isolated as hydrochloride salts of carboxylic acids (32 and 33), or as neutral carboxylic acid compounds (34 and 35).
  • products 30 and 31 are initially isolated in the form of esters (36 and 37) which are subsequently hydrolyzed with boiling sodium hydroxide. Acids 30 and 31 are then isolated as hydrochloride salts. All carboxylic acids 30-35 are finally reacted with a primary or secondary amine to form the corresponding secondary or tertiary amide.
  • Reaction conditions a) arylboronic acid 28 or 29, Pd(dppf)Cl 2 .DCM, Na 2 CO 3 , dioxane/water (4: 1), Ar, 110 °C, 72 hours; b) 2M NaOH (sodium hydroxide), MeOH, 110 °C, 24 hours; c) primary or secondary amine, EDC.HC1 (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), HOBt.H 2 O (1-hydroxybenzotriazole hydrate), DIPEA (AN-diisopropylethylamine).
  • the LC-MS system consists of a binary pump HHG-3400RS which is connected to a vacuum degasser, of a heated column compartment TCC-3000, an autosampler WTS-3000 and an ultraviolet detector VWD-3000.
  • the quadrupole mass spectrometer was equipped with an electron-spray ionization source and the data were recorded in positive mode with the following parameters: spray voltage was 3.2 kV, capillary temperature was 350 °C, gas temperature was 300 °C.
  • Example 2 Preparation of compounds of formula I derived from 1H-pyrrolo [2, 3-b] pyridine or from 1H-pyrazolo [3 ,4-b] pyridine, wherein the primary or secondary amine in position 2 or 3 of the basic ring is attached by a carbonyl bridge.
  • the mixture was diluted with water and the aqueous phase of the resulting acids 30-35 was washed twice with EA (2 c 100 mL) and then twice with DCM (2 c 100 mL).
  • the resulting aqueous phase was carefully acidified with 10% HCI to pH ⁇ 1.
  • the resulting precipitate was filtered, carefully rinsed with water (3 c 15 mL) followed by hexane (3 c 20 mL) to give pure carboxylic acids 32 and 33 as hydrochloride salts, and carboxylic acids 34 and 35 as neutral compounds.
  • Carboxylic acid 31 (95 mg; 0.250 mmol); EDC.HC1 (48 mg; 0.250 mmol); HOBt.H 2 O (42 mg; 0.275 mmol); DIPEA (131 ⁇ L; 0.750 mmol) and benzylamine (27 ⁇ L; 0.250 mmol) in 5 mL anhydrous THF. After the extraction, the reaction mixture was purified by column chromatography using mobile phase (DCM/EA) (1:1), to yield pure product 7 as a brownish solid. Yield 44%.
  • DCM/EA mobile phase
  • Carboxylic acid 30 (85 mg; 0.242 mmol); EDC.HC1 (46 mg; 0.242 mmol); HOBt.H 2 0 (41 mg; 0.266 mmol); DIPEA (126 ⁇ L; 0.725 mmol) and 1-phenylpiperidine (39 mg; 0.242 mmol) in 5 mL anhydrous THF.
  • the reaction mixture was purified by column chromatography using mobile phase (DCM/EA) (1: 1). The purified mixture was then precipitated from MeOH to yield pure product 10 as white solid. Yield 32%.
  • Carboxylic acid 32 (110 mg; 0.312 mmol); EDC.HC1 (60 mg; 0.312 mmol); HOBt.H 2 0 (53 mg; 0.343 mmol); DIPEA (163 ⁇ L; 0.936 mmol) and 1-ethylpiperazine (40 ⁇ L; 0.312 mmol) in 5 mL anhydrous THF. After the extraction, the reaction mixture was purified by column chromatography using mobile phase DCM/MeOH/NH 4 OH (25% aqueous solution) (15: 1:0.1) to yield pure product 12 as brownish solid. Yield 60%.
  • Carboxylic acid 32 (97 mg; 0.275 mmol); EDC.HC1 (53 mg; 0.275 mmol); HOBt.H 2 0 (46 mg; 0.302 mmol); DIPEA (144 ⁇ L; 0.825 mmol) and 1-phenylpiperidine (44 mg; 0.275 mmol) in 5 mL anhydrous THF. After the extraction, the reaction mixture was purified by column chromatography using mobile phase (DCM/EA) (1: 1) to yield pure product 13 as white solid. Yield 28%.
  • DCM/EA mobile phase
  • Carboxylic acid 33 (99 mg; 0.260 mmol); EDC.HC1 (50 mg; 0.260 mmol); HOBt.H 2 0 (44 mg; 0.286 mmol); DIPEA (136 ⁇ L; 0.780 mmol) and benzylamine (28 ⁇ L; 0.260 mmol) in 5 mL anhydrous THF. After the extraction, the resulting mixture was directly precipitated in MeOH, to yield pure product 14 as white solid. Yield 73%.
  • Carboxylic acid 35 (128 mg; 0.370 mmol); EDC.HC1 (71 mg; 0.370 mmol); HOBt.H 2 0 (62 mg; 0.410 mmol); DIPEA (193 ⁇ L; 1.11 mmol) and benzylamine (41 ⁇ L; 0.370 mmol) in 5 mL anhydrous THF. After the extraction, the reaction mixture was purified by column chromatography using mobile phase (DCM/EA) (1: 1) to yield pure product 17 as white solid. Yield 25%.
  • DCM/EA mobile phase
  • Example 3 Determination of the decrease in proliferation of tumor cell lines by the action of the inhibitor alone, and potentiation of the effect of cisplatin by the inhibitor
  • the cell lines were: Jurkat (acute T- leukemia), MOLT-4 (acute lymphoblastic leukemia), A549 (pulmonary adenocarcinoma), HT-29 (colorectal adenocarcinoma), PANC -1 (pancreatic cancer), A2780 (ovarian cancer), HeLa (cervical cancer), MCF-7 (breast adenocarcinoma) and SAOS-2 (osteosarcoma).
  • the lines were purchased from ATCC (Manassas, USA) and Sigma- Aldrich (St. Louis, USA) and maintained according to the supplier's recommendations. All lines were cultured in an incubator at a constant temperature of 37 °C and a controlled air atmosphere with 5% carbon dioxide. Exponentially growing cells up to a maximum of the twentieth passage were used during the study.
  • the cells were resuspended and seeded at an optimal density of 1 c 10 3 to 50* 10 3 cells per well (determined from preliminary experiments) in 96-well plates (TPP, Trasadingen, Switzerland), to the bottoms of which they adhered by the next day. For the next 48 hours, the cells were cultured in test substance medium at a final concentration of 10 mM. Doxorubicin (Sigma-Aldrich, St. Louis, USA) at a final concentration of 1 mM was used as a positive control for the standard testing procedure.
  • the cell lines were again cultured for 48 hours with a test substance (10 pM) together with cisplatin, which was used according to the sensitivity of the respective cell line at a concentration of 2 pM (MOLT-4, Jurkat, A2780), 10 pM (MCF-7) and 15 pM (A549, HT-29, HeLa, SAOS-2, PANC-1).
  • a test substance 10 pM
  • MCF-7 10 pM
  • 15 pM A549, HT-29, HeLa, SAOS-2, PANC-1).
  • the standard ATR kinase inhibitor VE-821 was used to compare efficacy.
  • Table 1 shows the decrease in proliferation of Jurkat, MOLT-4, A549, HT-29, PANC-1, A2780, HeLa, MCF-7, SAOS-2 tumor cell lines by the action of compounds of formula I compared to the VE 821 standard at 10 mM concentration.
  • the decrease in proliferation of the cells treated with compounds of formula I is expressed as a percentage of the proliferation of control cells treated with solvent only (0.1% DMSO) (100%).
  • Table 2 shows the potentiation of the effect of cisplatin on Jurkat, MOLT 4, A549, HT-29, PANC-1, A2780, HeLa, MCF-7, SAOS-2 tumor cell lines.
  • the table includes cisplatin alone, the compound of formula I alone and the combination of the compound of formula I with cisplatin.
  • the decrease in proliferation of the cells treated with compounds of formula I and cisplatin is expressed as a percentage of the proliferation of control cells treated with solvent only (0.1% DMSO) (100%).
  • Cisplatin at the concentration used (2 to 15 pM) reduces cell proliferation to 40 to 80% of control cell proliferation.
  • the novel inhibitors increased its cytotoxic properties, leading to a further decrease in proliferation in the tumor cell lines MOLT 4, A459, HT-29, PANC-1, A2780, HeLa, MCF-7, SAOS-2.
  • Table 1 Decrease of proliferation in tumor cell lines Jurkat, MOLT-4, A549, HT-29, PANC-1, A2780, HeLa, MCF-7, SAOS-2 by the action of the inibitors (10 mM) alone, in comparison with VE-821 (10 pM) standard, expressed as % of control cell proliferation (100%).
  • Table 2 Potentiation of the effect of cisplatin by the inhibitor (10 mM) compared to the action of the inhibitor alone and cisplatin alone, on tumor cell lines MOLT-4, A549, HT-29, HeLa, SAOS-2, PANC-1, A2780 and MCF-7.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un composé hétérocyclique d'azote de formule générale I, dans laquelle X est C ou N ; R1 est choisi parmi les groupes alkyle en C1-C6 ; Z- est -CH2- ou – C(O)- ; R2 est choisi dans le groupe comprenant anilino ; anilino substitué par un groupe di(alkyle en C1-C6)amino en position 2, 3, ou 4 ; benzylamino ; benzylamino substitué par un groupe di(alkyle en C1-C6)amino en position 2, 3, ou 4 ; 4-phénylpipéridin-1-yle, 1-(alkyle en C1-C6)pipérazin-4-yle, 1,2,3,4-tétrahydroisoquinolinyle ; 1-(alcanesulfonyle en C1-C6)pipérazin-4-yle ; 4-[4-(alkyle en C1-C6)-pipérazin-1-yl]pipéridin-1-yle ; et des sels pharmaceutiquement acceptables de ceux-ci avec des métaux alcalins, ou des sels d'addition de ceux-ci avec des acides. Ces composés sont des inhibiteurs de kinase ATR, appropriés en particulier pour le traitement de maladies tumorales, en monothérapie ainsi qu'en combinaison avec une autre chimiothérapie ou avec une radiothérapie. (I)
PCT/CZ2022/050002 2021-05-10 2022-01-12 Composés antitumoraux à base d'hétérocycles d'azote et leur utilisation en tant que médicaments Ceased WO2022237922A1 (fr)

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CZ2021-230A CZ309579B6 (cs) 2021-05-10 2021-05-10 Protinádorové sloučeniny na bázi dusíkatých heterocyklů, jejich použití jako léčiv a farmaceutické přípravky je obsahujíci

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025133961A1 (fr) * 2023-12-21 2025-06-26 Pfizer Inc. Composés hétéroaryle azotés pour traiter des maladies chroniques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028724A1 (fr) * 2001-10-04 2003-04-10 Smithkline Beecham Corporation Inhibiteurs de la kinase chk1
WO2012178124A1 (fr) * 2011-06-22 2012-12-27 Vertex Pharmaceuticals Incorporated Composés utiles comme inhibiteurs de la kinase atr

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028724A1 (fr) * 2001-10-04 2003-04-10 Smithkline Beecham Corporation Inhibiteurs de la kinase chk1
WO2012178124A1 (fr) * 2011-06-22 2012-12-27 Vertex Pharmaceuticals Incorporated Composés utiles comme inhibiteurs de la kinase atr

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BLACKFORD, ANDREW N.STEPHEN P. JACKSON: "ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response", MOLECULAR CELL, vol. 66, no. 6, 2017, pages 801 - 817, XP085076460, DOI: 10.1016/j.molcel.2017.05.015
GORECKI, LUKASMARTIN ANDRSJAN KORABECNY: "Clinical Candidates Targeting the ATR-CHK1-WEE1 Axis in Cancer", CANCERS, vol. 13, no. 4, 2021, pages 795
GORECKI, LUKASMARTIN ANDRSMARTINA REZACOVAJAN KORABECNY: "Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy", PHARMACOLOGY & THERAPEUTICS, 2020, pages 107518, XP055895241, DOI: 10.1016/j.pharmthera.2020.107518
JACKSON, STEPHEN P.JIRI BARTEK: "The DNA-damage response in human biology and disease", NATURE, vol. 461, no. 7267, 2009, pages 1071 - 1078, XP055070409, DOI: 10.1038/nature08467
LECONA, EMILIOOSCAR FERNANDEZ-CAPETILLO: "Targeting ATR in cancer", NATURE REVIEWS CANCER, vol. 18, no. 9, 2018, pages 586 - 595, XP036572874, DOI: 10.1038/s41568-018-0034-3
SALDIVAR, JOSHUA C.DAVID CORTEZKARLENE A. CIMPRICH: "The essential kinase ATR: ensuring faithful duplication of a challenging genome", NATURE REVIEWS. MOLECULAR CELL BIOLOGY, vol. 18, no. 10, 2017, pages 622 - 636

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025133961A1 (fr) * 2023-12-21 2025-06-26 Pfizer Inc. Composés hétéroaryle azotés pour traiter des maladies chroniques

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