8XAM

Co-crystal structure of compound 7 in complex with MAT2A

Summary for 8XAM

• Entry DOI: 10.2210/pdb8xam/pdb
• Descriptor: S-adenosylmethionine synthase isoform type-2, S-ADENOSYLMETHIONINE, 2-[3-[7-chloranyl-4-(dimethylamino)-2-oxidanylidene-quinazolin-1-yl]phenoxy]-~{N}-[3-[7-chloranyl-4-(dimethylamino)-2-oxidanylidene-quinazolin-1-yl]phenyl]ethanamide, ... (4 entities in total)
• Functional Keywords: mat2a inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 85470.96

Authors

Gao, F.,Ding, X. (deposition date: 2023-12-04, release date: 2024-02-28)

Primary citation

Gao, F.,Ding, X.,Cao, Z.,Zhu, W.,Fan, Y.,Steurer, B.,Wang, H.,Cai, X.,Zhang, M.,Aliper, A.,Ren, F.,Ding, X.,Zhavoronkov, A.
Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach.
Bioorg.Med.Chem., 100:117633-117633, 2024

PubMed Abstract: 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.

PubMed: 38342078
DOI: 10.1016/j.bmc.2024.117633

Experimental method

X-RAY DIFFRACTION (1.3 Å)