Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer

Chengbin Yang; Menghui Wang; Yimin Gong; Mingli Deng; Yun Ling; Qingquan Li; Jianxin Wang; Yaming Zhou

doi:10.1016/j.bioorg.2023.106779

Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer

Bioorg Chem. 2023 Nov:140:106779. doi: 10.1016/j.bioorg.2023.106779. Epub 2023 Aug 9.

Authors

Chengbin Yang¹, Menghui Wang², Yimin Gong³, Mingli Deng³, Yun Ling³, Qingquan Li², Jianxin Wang⁴, Yaming Zhou⁵

Affiliations

¹ Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China; Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China.
² Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
³ Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China.
⁴ Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China. Electronic address: jxwang@fudan.edu.cn.
⁵ Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China. Electronic address: ymzhou@fudan.edu.cn.

PMID: 37579621
DOI: 10.1016/j.bioorg.2023.106779

Abstract

Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

Keywords: Azaindole; Breast cancer; Cyclin-dependent kinase; PI3K inhibitors; Phosphatidylinositol 3-kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase 2
Humans
Phosphatidylinositol 3-Kinases* / metabolism
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Triple Negative Breast Neoplasms* / metabolism

Substances

Phosphatidylinositol 3-Kinases
Phosphoinositide-3 Kinase Inhibitors
CDK2 protein, human
Cyclin-Dependent Kinase 2