1. Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction.
- Author
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Chen, Danqi, Chen, Yuehong, Lian, Fulin, Chen, Liu, Li, Yanlian, Cao, Danyan, Wang, Xin, Chen, Lin, Li, Jian, Meng, Tao, Huang, Min, Geng, Meiyu, Shen, Jingkang, Zhang, Naixia, and Xiong, Bing
- Subjects
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PROTEIN-protein interactions , *TARGETED drug delivery , *PHOSPHODIESTERASE inhibitors , *CELLULAR signal transduction , *SMALL molecules - Abstract
Abstract Although mutated Ras protein is well recognized as an important drug target, direct targeting Ras has proven to be a daunting task. Recent studies demonstrated that Ras protein needs PDEδ to relocate to plasma membrane to execute its signaling transduction function, which provides a new avenue for modulating the Ras protein. To find small molecules antagonizing the interactions between PDEδ and Ras, here we presented a successful application of fragment-based drug discovery of PDEδ inhibitors. Under the guidance of crystal structures, we are able to quickly optimize the initial fragment into highly potent inhibitors, with more than 2000-fold improvement in binding activity, which further adds to the arsenal towards the inhibition of Ras signaling in cancer therapy. Graphical abstract Image 1 Highlights • Fragment-based approach was used to discover a new chemotype targeting PDEδ-Ras interaction. • Scaffold modification was undertaken on the basis of co-crystal structure and resulted in an optimizable hit. • Two rounds of optimization quickly improved the binding activity by more than 1000 fold. • Biological study indicates the PDEδ-Ras inhibitor could affect the downstream Ras signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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