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, NTQ1062 (compound 22b) 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 NTQ1062 demonstrated that it possesses good oral pharmacokinetic characteristics
and dose-dependent pharmacodynamic effects on downstream biomarkers.
In addition, NTQ1062 exhibits a robust antitumor efficacy
in xenograft models in which the PI3K-Akt-mTOR pathway was activated.
Based on its ideal druglike properties, NTQ1062 is currently
being evaluated in a phase I clinical trial for the treatment of advanced
solid tumors (CTR20211999).