MD_DATA_PRMT_5
Year: 2024
Type: article
Abstract: The PRMT5-MTA complex, which is uniquely present in cancer cells with MTAP gene deletions, represents a compelling target for synthetic lethality strategies in cancer therapy. Despite the identification of PRMT5-MTA inhibitors to date, none have advanced to clinical use, and the chemical diversity among these inhibitors remains limited. Therefore, there is a pressing need for structurally novel inhibitors. Herein, we report the discovery of new PRMT5-MTA inhibitors identified through structure-based virtual screening. Among these, compound 14 demonstrated subnanomolar binding affinity for the PRMT5-MTA complex with 11.7-fold selectivity over the PRMT5-SAM complex (MTA+ KD = 0.236 μM, SAM+ KD = 2.77 μM, ratio = 11.7×). Molecular dynamics (MD) simulations provided insights into the binding mode of compound 14 with the PRMT5 protein, facilitating the identification of derivatives 88 and 108, thereby expanding the chemical space of hit compounds. Our findings not only enhance the chemical diversity of PRMT5-MTA selective inhibitors but also deepen the understanding of the structure-activity relationship (SAR) governing PRMT5 selectivity. The discovered compounds represent promising starting points for the development and optimization of novel PRMT5-MTA inhibitors.
Source: Figshare
Author: yang, chen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6958498110
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