7KCE

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 2

7KCE の概要

• エントリーDOI: 10.2210/pdb7kce/pdb
• 関連するPDBエントリー: 7KCC 7KCF 7KDA 7KDB
• 分子名称: S-adenosylmethionine synthase isoform type-2, 5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• 機能のキーワード: methionine adenosyltransferase, s-adenosylmethionine synthase isoform type-2, sam, allosteric inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44542.93

構造登録者

Padyana, A.,Jin, L. (登録日: 2020-10-05, 公開日: 2021-04-21, 最終更新日: 2023-10-18)

主引用文献

Konteatis, Z.,Travins, J.,Gross, S.,Marjon, K.,Barnett, A.,Mandley, E.,Nicolay, B.,Nagaraja, R.,Chen, Y.,Sun, Y.,Liu, Z.,Yu, J.,Ye, Z.,Jiang, F.,Wei, W.,Fang, C.,Gao, Y.,Kalev, P.,Hyer, M.L.,DeLaBarre, B.,Jin, L.,Padyana, A.K.,Dang, L.,Murtie, J.,Biller, S.A.,Sui, Z.,Marks, K.M.
Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion.
J.Med.Chem., 64:4430-4449, 2021

PubMed Abstract: The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase () gene, which is adjacent to the tumor suppressor and codeleted with in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10 000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, -adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of -null cells both in tissue culture and xenograft tumors. These data supported progressing into current clinical studies (ClinicalTrials.gov NCT03435250).

PubMed: 33829783
DOI: 10.1021/acs.jmedchem.0c01895

実験手法

X-RAY DIFFRACTION (1.14 Å)