Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors

Ning Zhang; Zhimei Yu; Xiaohong Yang; Yan Zhou; Jia Wang; Shao-Lin Zhang; Ming-Wei Wang; Yun He

doi:10.1016/j.ejmech.2018.09.002

Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors

Eur J Med Chem. 2018 Oct 5:158:707-719. doi: 10.1016/j.ejmech.2018.09.002. Epub 2018 Sep 6.

Authors

Ning Zhang¹, Zhimei Yu¹, Xiaohong Yang¹, Yan Zhou², Jia Wang², Shao-Lin Zhang³, Ming-Wei Wang⁴, Yun He⁵

Affiliations

¹ School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
² The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China.
³ School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: zhangsl@cqu.edu.cn.
⁴ The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China. Electronic address: mwwang@simm.ac.cn.
⁵ School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: yun.he@cqu.edu.cn.

PMID: 30245395
DOI: 10.1016/j.ejmech.2018.09.002

Abstract

Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC₅₀ = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC₅₀ value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC₅₀ value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.

Keywords: Anticancer drug; Phosphatidylinositol 3-kinase; Structure-activity relationship.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Neoplasms / drug therapy
Phosphatidylinositol 3-Kinases / genetics*
Phosphoinositide-3 Kinase Inhibitors*
Point Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors