imino-methyl-[1-[6-(3-methylmorpholin-4-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-lambda6-sulfane | 1352226-88-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: imino-methyl-[1-[6-(3-methylmorpholin-4-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-lambda6-sulfane
• 英文别名: imino-methyl-[1-[6-(3-methylmorpholin-4-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane
• CAS: 1352226-88-0
• 化学式: C₂₀H₂₄N₆O₂S
• 分子量: 412.5
• InChiKey: OHUHVTCQTUDPIJ-UHFFFAOYSA-N

物化性质

• 密度：
  1.52±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

Ceralasertib（AZD6738）是一种口服、活性的选择性ATR激酶抑制剂，IC50值为1 nM。其在Phase 1/2试验中表现出良好效果。

靶点

Target	Value
ATR (Cell-free assay)	1 nM

体外研究

Ceralasertib在四个KRAS突变细胞系（H23、H460、A549和H358）中抑制了ATR激酶活性，并损害了细胞活性。在缺乏ATM的H23细胞中，它显著增强了顺铂诱导的快速细胞死亡作用。对于p53或ATM缺失的细胞，在Ceralasertib治疗下，复制叉停滞和未修复DNA损伤积累导致有丝分裂障碍，最终引发细胞死亡。

体内研究

在携带H460和H23肿瘤的小鼠中，Ceralasertib（50 mg/kg，口服）导致了肿瘤生长抑制（TGI），与顺铂联合使用时显著促进了ATM缺失的H23肿瘤快速退化。在LoVo异种移植物小鼠模型中，Ceralasertib（50 mg/kg）结合辐射（2 Gy）并未引起毒性，同时保持了疗效。

文献信息

• AN INHIBITOR OF ATR KINASE FOR USE IN A METHOD OF TREATING A HYPER-PROLIFERATIVE DISEASE
  申请人：Bayer Aktiengesellschaft

  公开号：US20200063212A1

  公开（公告）日：2020-02-27

  The present invention covers 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyra-zol-5-yl)-1,7-naphthyridine (in the following called “Compound A”), an inhibitor of ATR kinase, for use in a method of treating a hyper-proliferative disease in a subject. Preferably the hyper-proliferative disease or the subject is characterized by one or more biomarker(s) selected from a) one or more functional mutation(s) in one or more gene(s)/protein(s) selected from APC, ATG5, ARID1A, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRAF, BRCA1, BRCA2, BRIP1, CCND1, CCNE1, CCNE2, CDC7, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, DYRK1A, EGFR, ERBB2, ERBB3, ERCC2, ERCC3, ERCC4, ER-CC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, HDAC2, H2AFX, HRAS, KRAS, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, MYC, NBN, NRAS, PALB2, PARP1, PARP2, PARP3, PARP4, PCNA, PIK3CA, PMS2, POLA1, POLB, POLH, POLL, POLN, POLQ, PRKDC, PTEN, RAD9A, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TM-PRSS2, TMPRSS2-ERG, TOPBP1, TOP2A, TOP2B, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XR-CC1 XRCC2, XRCC3, XRCC4 and/or XRCC6 gene/protein; and/or b) the activation of the ALT pathway; and/or c) microsatellite instability. The present invention also covers a kit comprising Compound A together with means to detect one or more of the afore-biomarker(s) and a method for identifying a subject having a hyper-proliferative disease disposed to respond favorably to Compound A, wherein the method comprises the detection of one or more of the aforementioned biomarker(s). Further, the invention covers a method of determining whether a subject having a hyper-proliferative disease will respond to the treatment with Compound A, wherein the method comprises the detection of one or more of the aforementioned biomarker(s) in a sample of the subject.
• PREDICTIVE MARKERS FOR ATR KINASE INHIBITORS
  申请人：Bayer Aktiengesellschaft

  公开号：US20200375997A1

  公开（公告）日：2020-12-03

  The present invention covers an ATR kinase inhibitor, particularly 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(H-pyrazol-5-yl)-1,7-naphthyridine (“Compound A”), for use in the treatment of a hyper-proliferative disease in a subject, wherein the hyper-proliferative disease or the subject is or has been characterized by one or more biomarker(s), wherein the biomarker(s) comprise(s) a) one or more functional mutations in one or more gene(s)/protein(s) selected from RBBP8, APOBEC3A, APOBEC3B, CLSPN, ERCC, HUS1, MAD2L2, PGBD5, POLD1, RAD1, TIMELESS and/or TIPIN; and/or b) the expression of a fusion gene encoding a fusion protein selected from EWSR-ERG, EWSR1-FLI1, SS18-SSX and/or SS18-SSX2 gene/protein.
• COMBINATION OF ATR KINASE INHIBITORS AND PD-1/PD-L1 INHIBITORS
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：US20210128723A1

  公开（公告）日：2021-05-06

  The present invention covers combinations of at least two components, component A and component B, comprising component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described herein, a compound of general formula (lb) described herein and Compound A described infra, and component B being a PD-1/PD-L1 inhibitor described herein. Another aspect of the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particurlarly for the treatment of a hyper-proliferative disease.
• COMBINATION OF ATR KINASE INHIBITORS WITH 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE COMPOUNDS
  申请人：Bayer Aktiengesellschaft

  公开号：US20210369724A1

  公开（公告）日：2021-12-02

  The present invention relates to combinations of: component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1) or (A2) as defined herein, or a stereoisomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; and component B: one or more ATR kinase inhibitor(s) as defined herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; and, optionally, component C: one or more further pharmaceutical agent(s); and, optionally, in which either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
• COMBINATION THERAPY UTILIZING DNA ALKYLATING AGENTS AND ATR INHIBITORS
  申请人：Merck Patent GmbH

  公开号：US20210369705A1

  公开（公告）日：2021-12-02

  The present invention relates to synergistic combinations of DNA-alkylating ADCs and ATR inhibitors.