Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.
Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.
复制标题
使用结构引导的药物设计的新型体内活性CHK1抑制剂的鉴定。
DOI：
10.18632/oncotarget.5929
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发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Wood M
中科院分区：
文献类型：
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作者：
Massey AJ;Stokes S;Browne H;Foloppe N;Fiumana A;Scrace S;Fallowfield M;Bedford S;Webb P;Baker L;Christie M;Drysdale MJ;Wood M
Chk 1激酶是DNA损伤反应检查点的关键组分，特别是在癌细胞中，靶向Chk 1是增强DNA损伤化疗药物的抗肿瘤活性的潜在治疗机会。通过结构指导设计进行片段精细化来鉴定和开发一系列新型Chk 1抑制剂，最终鉴定出V158411，这是一种Chk 1和Chk 2激酶的强效ATP竞争性抑制剂。V158411消除吉西他滨和喜树碱诱导的细胞周期检查点，导致预期的细胞周期蛋白调节和癌细胞中细胞死亡增加。V158411在体外增强吉西他滨、顺铂、SN 38和喜树碱对多种p53缺陷型人肿瘤细胞系的细胞毒性，而p53活性细胞不受影响。在裸鼠中，V158411单药和与伊立替康联合给药显示出极轻微的毒性。在荷瘤动物中，在肿瘤中检测到高水平的V158411，消除半衰期较长;通过药代动力学特征分析，未发现与伊立替康的显著体内药物相互作用。V158411增强了伊立替康在各种人结肠肿瘤异种移植模型中的抗肿瘤活性，且无额外的全身毒性。这些结果证明了将V158411与标准护理化学治疗剂组合以增强这些药剂的治疗功效而不增加其对正常细胞的毒性的机会。因此，V158411需要进一步的临床评价。
Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.