Loading…

Rational Design of a Novel 6H-Benzocchromen Series as Selective PI3Kα Inhibitors

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A selective PI3Kα inhibitor may provide the opportunity to spare patients the sid...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2024-09, Vol.67 (17), p.15387
Main Authors: Shi, Xue, Feng, Heng, Tian, Haigang, Ma, Haibiao, Pang, Xiaomeng, Mao, Chenhan, Xiang, Peng, Xu, Zhengze, Han, Weidong, Yan, Yuxiang, Chen, Wei, Nan, Yuqing, Nan, Guanjun, Hu, Zhenyue, Hui, Lingyun, Li, Chenglong, Li, Yiping
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A selective PI3Kα inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a novel series of selective PI3Kα inhibitors using structure-based drug design and molecular docking to inform the design of 6H-benzo[c]chromen inhibitors. XJTU-L453 (21) was identified with PI3Kα inhibitory potency and unique selectivity over other PI3K isoforms and all other kinases tested. Further evaluation of pharmacokinetic properties and in vivo efficacy led to the identification of the preclinical potential of XJTU-L453 (21).The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A selective PI3Kα inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a novel series of selective PI3Kα inhibitors using structure-based drug design and molecular docking to inform the design of 6H-benzo[c]chromen inhibitors. XJTU-L453 (21) was identified with PI3Kα inhibitory potency and unique selectivity over other PI3K isoforms and all other kinases tested. Further evaluation of pharmacokinetic properties and in vivo efficacy led to the identification of the preclinical potential of XJTU-L453 (21).
ISSN:1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00992