Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers,Journal of Medicinal Chemistry

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Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-05 , DOI: 10.1021/acs.jmedchem.1c01319
Takayuki Irie ₁ , Tokiko Asami ₁ , Ayako Sawa ₁ , Yuko Uno ₁ , Chika Taniyama ₂ , Yoko Funakoshi ₂ , Hisao Masai ₃ , Masaaki Sawa ₁

Affiliation

CDC7, a serine-threonine kinase, plays conserved and important roles in regulation of DNA replication and has been recognized as a potential anticancer target. We report here the optimization of a series of furanone analogues starting from compound 1 with a focus on ADME properties suitable for clinical development. By replacing the 2-chlorobenzene moiety in 1 with various aliphatic groups, we identified compound 24 as a potent CDC7 inhibitor with excellent kinase selectivity and favorable oral bioavailability in multiple species. Oral administration of 24 demonstrated robust in vivo antitumor efficacy in a colorectal cancer xenograft model. Compound 24 (AS-0141) is currently in phase I clinical trials for the treatment of solid cancers.

中文翻译：

发现 AS-0141，一种用于治疗实体癌的 CDC7 激酶的强效选择性抑制剂

CDC7 是一种丝氨酸-苏氨酸激酶，在调节 DNA 复制方面发挥着保守和重要的作用，已被公认为潜在的抗癌靶点。我们在此报告了从化合物1开始的一系列呋喃酮类似物的优化，重点是适用于临床开发的 ADME 特性。通过更换在2氯苯基部分1与各种脂族基团，我们确定了化合物24，与在多个物种优良激酶选择性和有利的口服生物利用度的有效CDC7抑制剂。在结直肠癌异种移植模型中，口服24证明了强大的体内抗肿瘤功效。化合物24 （AS-0141）目前处于治疗实体癌的 I 期临床试验阶段。

更新日期：2021-10-14

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