Innovation Department of the Research Institute, Nanjing Chia-Tai Tianqing Pharmaceutical Co., Ltd., Nanjing 210046, P. R. China.
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2022 Jun 23;65(12):8144-8168. doi: 10.1021/acs.jmedchem.2c00527. Epub 2022 Jun 9.
Akt has emerged as an exciting target in oncology due to its critical roles in proliferation, survival, metabolism, metastasis, and invasion in tumor cells. Herein, we describe the discovery and optimization of a series of ATP-competitive Akt inhibitors that possess new chemical scaffolds and exhibit potent enzymatic activities and improved in vivo pharmacokinetic profiles. Remarkably, (compound ) exhibited potent antitumor efficacies in vitro and in vivo, which was accomplished through the optimization of the hinge binder region and the linkage. Subsequent studies of demonstrated that it possesses good oral pharmacokinetic characteristics and dose-dependent pharmacodynamic effects on downstream biomarkers. In addition, exhibits a robust antitumor efficacy in xenograft models in which the PI3K-Akt-mTOR pathway was activated. Based on its ideal druglike properties, is currently being evaluated in a phase I clinical trial for the treatment of advanced solid tumors (CTR20211999).
Akt 已成为肿瘤学中一个令人兴奋的靶点，因为它在肿瘤细胞的增殖、存活、代谢、转移和侵袭中发挥着关键作用。在此，我们描述了一系列 ATP 竞争性 Akt 抑制剂的发现和优化，这些抑制剂具有新的化学结构骨架，表现出强大的酶活性和改善的体内药代动力学特征。值得注意的是，化合物在体外和体内均表现出强大的抗肿瘤疗效，这是通过优化铰链结合区和连接键来实现的。随后对化合物的研究表明，它具有良好的口服药代动力学特征和对下游生物标志物的剂量依赖性药效学作用。此外，化合物在激活 PI3K-Akt-mTOR 通路的异种移植模型中表现出强大的抗肿瘤疗效。基于其理想的类药性，目前正在进行一项 I 期临床试验，以评估其治疗晚期实体瘤的疗效（CTR20211999）。
