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Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.

De Fusco C, Schimpl M, Börjesson U, Cheung T, Collie I, Evans L, Narasimhan P, Stubbs C, Vazquez-Chantada M, Wagner DJ, Grondine M, Sanders MG, Tentarelli S, Underwood E, Argyrou A, Smith JM, Lynch JT, Chiarparin E, Robb G, Bagal SK, Scott JS
J Med Chem 64 6814-6826 (2021)
Related entries: 7bhr, 7bht, 7bhu, 7bhv, 7bhw, 7bhx

Cited: 8 times
EuropePMC logo PMID: 33900758

Abstract

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound

Reviews citing this publication (4)

  1. Targeting allosteric regulation of cancer metabolism. Kremer DM, Lyssiotis CA. Nat Chem Biol 18 441-450 (2022)
  2. Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy. Guo J, Yang Y, Buettner R, Rosen ST. Curr Opin Oncol 34 546-551 (2022)
  3. MTAP loss: a possible therapeutic approach for glioblastoma. Patro CPK, Biswas N, Pingle SC, Lin F, Anekoji M, Jones LD, Kesari S, Wang F, Ashili S. J Transl Med 20 620 (2022)
  4. The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality. Bray C, Balcells C, McNeish IA, Keun HC. Front Oncol 13 1264785 (2023)

Articles citing this publication (4)

  1. Human Mat2A Uses an Ordered Kinetic Mechanism and Is Stabilized but Not Regulated by Mat2B. Bailey J, Douglas H, Masino L, de Carvalho LPS, Argyrou A. Biochemistry 60 3621-3632 (2021)
  2. Genomic landscape of non-small-cell lung cancer with methylthioadenosine phosphorylase (MTAP) deficiency. Ashok Kumar P, Graziano SL, Danziger N, Pavlick D, Severson EA, Ramkissoon SH, Huang RSP, Decker B, Ross JS. Cancer Med 12 1157-1166 (2023)
  3. Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors. Li Q, Zang Y, An D, Liu L, Jiang W, Liu R, Su J, Yang J, Li L, Zhang X. ACS Med Chem Lett 14 1876-1881 (2023)
  4. Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss. Bou Zerdan M, Ashok Kumar P, Haroun E, Srivastava N, Ross J, Sivapiragasam A. Oncotarget 14 178-187 (2023)


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