8XAR

Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with SAM and Compound 54

Summary for 8XAR

• Entry DOI: 10.2210/pdb8xar/pdb
• Descriptor: S-adenosylmethionine synthase isoform type-2, 7-chloranyl-2-ethyl-5-pyridin-3-yl-pyrazolo[3,4-c]quinolin-4-one, GLYCEROL, ... (7 entities in total)
• Functional Keywords: transferase, one-carbon metabolism, metal-binding, inhibitor complex
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 46537.50

Authors

Zheng, J.Y.,Zhang, G.P.,Li, J.J.,Tong, S.L. (deposition date: 2023-12-05, release date: 2024-06-26)

Primary citation

Zheng, J.,Zhang, T.,Tong, S.,Liu, T.,Cui, J.,Xu, H.,Hu, D.,Shen, Y.,Yin, Y.,Zhao, D.,Tan, C.,Dong, X.,Chen, J.,Ji, F.,Tong, C.,Li, J.J.,Li, J.,Zhang, G.
Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.
J.Med.Chem., 67:9431-9446, 2024

PubMed Abstract: Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound , which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, demonstrates excellent brain exposure with a of 0.64 in rats.

PubMed: 38818879
DOI: 10.1021/acs.jmedchem.4c00552

Experimental method

X-RAY DIFFRACTION (1.19 Å)