Design, Synthesis and Biological Activity of Novel 2,3,4,5-Tetra-Substituted Thiophene Derivatives as PI3Kα Inhibitors with Potent Antitumor Activity - Sophion

Design, Synthesis and Biological Activity of Novel 2,3,4,5-Tetra-Substituted Thiophene Derivatives as PI3Kα Inhibitors with Potent Antitumor Activity


Author(s): WeikeLiao, Zhongyuan Wang, Yufei Han, Yinliang Qi, Jiaan Liu, Juan Xie, Ye Tian, Qiancheng Leia, Rui Chen, Ming Sun, Lei Tang, Guowei Gong, Yanfang Zhao


Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms β, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.