2. Academic Validation
  3. Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

  • J Med Chem. 2023 Apr 13;66(7):4849-4867. doi: 10.1021/acs.jmedchem.2c02006.
Silong Zhang 1 2 3,  Luolong Qing 2,  Ziwei Wang 2,  Yu Zhang 2,  Yuanyuan Li 3 4,  Huaxiang Fang 3,  Yi Liu 2 4 5,  Huan He 1 2 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China.
  • 2 Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China.
  • 3 Wuhan Yuxiang Pharmaceutical Technology Company, Limited, Wuhan 430200, P. R. China.
  • 4 School of Life Science and Technology & School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, P. R. China.
  • 5 Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Hubei University of Science and Technology, Xianning 437100, P. R. China.
PMID: 36961373 DOI: 10.1021/acs.jmedchem.2c02006
Abstract

Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise Cancer treatment. Herein, we report the discovery of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC50 = 18 nM) and proliferation of MTAP-null Cancer cells (IC50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailability of 116% in mice. More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL-1. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model.

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