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

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

  • J Med Chem. 2022 Jun 23;65(12):8144-8168. doi: 10.1021/acs.jmedchem.2c00527.
Changyou Ma 1,  Jian Wu 1,  Lei Wang,  Xiaojun Ji 1,  Yebin Wu 1,  Lei Miao 1,  Donghui Chen 1,  Linlin Zhang 1,  Youzhi Wu 1,  Haiwei Feng 1,  Ying Tang 1,  Qiuhua Zhou 1,  Junjie Pei 1,  Xule Yang 2,  Dan Xu 1,  Qidong You,  Yuan Xie 2
Affiliations

Affiliations

  • 1 Innovation Department of the Research Institute, Nanjing Chia-Tai Tianqing Pharmaceutical Co., Ltd., Nanjing 210046, P. R. China.
  • 2 Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
PMID: 35679512 DOI: 10.1021/acs.jmedchem.2c00527
Abstract

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).

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