Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach.

The methionine adenosyltransferase MAT2A catalyzes the synthesis ofthe methyl donor S-adenosylmethionine (SAM) and thereby regulates critical aspects of metabolism and transcription. Aberrant MAT2A function can lead to metabolic and transcriptional reprogramming of cancer cells, and MAT2A has been shown to promote survival of MTAP-deficient tumors, a genetic alteration that occurs in ∼ 13 % of all tumors. Thus, MAT2A holds great promise as a novel anticancer target. Here, we report a novel series of MAT2A inhibitors generated by a fragment growing approach from AZ-28, a low-molecular weight MAT2A inhibitor with promising pre-clinical properties. X-ray co-crystal structure revealed that compound 7 fully occupies the allosteric pocket of MAT2A as a single molecule mimicking MAT2B. By introducing additional backbone interactions and rigidifying the requisite linker extensions, we generated compound 8, which exhibited single digit nanomolar enzymatic and sub-micromolar cellular inhibitory potency for MAT2A. Copyright © 2024. Published by Elsevier Ltd.

Citation

Feng Gao, Xiaoyu Ding, Zhongying Cao, Wei Zhu, Yaya Fan, Barbara Steurer, Hailong Wang, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Xiao Ding, Alex Zhavoronkov. Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach. Bioorganic & medicinal chemistry. 2024 Feb 15;100:117633

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PMID: 38342078

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