AS-0141 的发现，一种有效的和选择性的 CDC7 激酶抑制剂，用于治疗实体瘤。
Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers.
机构信息
Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
Ginkgo Biomedical Research Institute, Research and Development Department, SBI Biotech Co., Ltd., Izumi Garden Tower 15F, 1-6- Roppongi, Minato-ku, Tokyo 106-6015, Japan.
出版信息
J Med Chem. 2021 Oct 14;64(19):14153-14164. doi: 10.1021/acs.jmedchem.1c01319. Epub 2021 Oct 5.
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 with a focus on ADME properties suitable for clinical development. By replacing the 2-chlorobenzene moiety in with various aliphatic groups, we identified compound as a potent CDC7 inhibitor with excellent kinase selectivity and favorable oral bioavailability in multiple species. Oral administration of demonstrated robust antitumor efficacy in a colorectal cancer xenograft model. Compound (AS-0141) is currently in phase I clinical trials for the treatment of solid cancers.
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而重要的作用，已被认为是一种有潜力的抗癌靶点。我们在此报告了一系列呋喃酮类似物的优化，以化合物 为起始，重点关注适合临床开发的 ADME 特性。通过用各种脂肪族基团取代化合物 中的 2-氯苯部分，我们鉴定出化合物 是一种有效的 CDC7 抑制剂，对激酶具有优异的选择性，并且在多种物种中具有良好的口服生物利用度。化合物 在结直肠癌细胞异种移植模型中进行口服给药，表现出强大的抗肿瘤疗效。化合物 （AS-0141）目前正在进行治疗实体瘤的 I 期临床试验。
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