Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors.

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).