4058-78-0Relevant academic research and scientific papers
Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction
Wang, Lei,Li, Li,Zhou, Zi-Han,Jiang, Zheng-Yu,You, Qi-Dong,Xu, Xiao-Li
, p. 63 - 73 (2017)
Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure–activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50?=?27?μM), a moderate binding capacity (KD?=?40?μM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549?cell lines (IC50?=?26?μM, 15?μM and 38?μM respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI.
