NIBS黄牛实验室、张二荃实验室和BIG杨运桂实验室合作发现FTO抑制剂entacapone通过调控FTO-FOXO1通路治疗代谢综合征

CryoEM structure of yeast cytoplasmic exosome complex.

Jun-Jie Liu^1,2,*, Chu-Ya Niu^1,*, Yao Wu^3,*, Dan Tan³, Yang Wang¹, Ming-Da Ye¹, Yang Liu^2,4, Wenwei Zhao⁴, Ke Zhou⁵, Quan-Sheng Liu⁵, Junbiao Dai⁶, Xuerui Yang⁴, Meng-Qiu Dong³, Niu Huang³ and Hong-Wei Wang¹

Discovery of 2-Acylaminothiophene-3-Carboxamides as Multitarget Inhibitors for BCR-ABL Kinase and Microtubules. Cao R¹, Wang Y¹, Huang N¹. ¹National Institute of Biological Sciences, Beijing , No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China. Abstract The emergence of drug resistance of the BCR-ABL kinase inhibitor imatinib, especially toward the T315I gatekeeper mutation, poses a great challenge to targeted therapy in treating chronic myeloid leukemia (CML) patients. To discover novel inhibitors against drug-resistant CML bearing T315I mutation, we applied a physics-based hierarchical virtual screening approach to dock a large chemical library against ATP binding pockets of both wild-type (WT) and T315I mutant ABL kinases in a combinatorial fashion. This strategy automatically resulted in 87 compounds satisfying structural and energetic criteria of both WT and T315I mutant kinases. Among them, nine compounds, which share a common thiophene-based scaffold and adopt similar binding poses, were chosen for experimental testing and one of them was shown to have low micromolar inhibition activities against both WT and mutant ABL kinases. Structure-activity relationship analysis with a series of structural modifications based on 2-acylaminothiophene-3-carboxamide scaffold supports our predicted binding mode. Interestingly, the same chemical scaffold was also enriched in our previous virtual screening campaign against colchicine site of microtubules using the same computational protocol, which suggests our virtual screening strategy is capable of discovering small-molecule ligands targeting distinct protein binding sites without sharing any sequential and structural similarity. Furthermore, the multitarget inhibition activity of this class of compounds was assessed in cellular experiments. We expect that the 2-acylaminothiophene-3-carboxamide scaffold may serve as a promising starting point for developing multitarget inhibitors in cancer treatment by targeting both kinases and microtubules.