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
  • 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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