Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors

  • ACS Med Chem Lett. 2023 Dec 4;14(12):1876-1881. doi: 10.1021/acsmedchemlett.3c00488.
Qun Li  1  2 ,  Yang Zang  1  2 ,  Dan An  1  2 ,  Lifei Liu  1  2 ,  Wen Jiang  1  2 ,  Rongchen Liu  1  2 ,  Jiangtao Su  3 ,  Jun Yang  1  2  4 ,  Lie Li  1  2 ,  Xuejun Zhang  1  2
Affiliations
  • 1. Hubei Bio-Pharmaceutical Industrial Technological Institute Inc., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei 430075, China.
  • 2. Humanwell Healthcare (Group) Co., Ltd., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei 430075, China.
  • 3. Hubei University of Technology, Wuhan, 430068, China.
  • 4. Humanwell Pharmaceuticals US Inc. 421 Sovereign Court, Ballwin, Missouri 63011, United States.
PMID: 38116423 DOI: 10.1021/acsmedchemlett.3c00488
Abstract

Inhibition of methionine adenosyltransferase 2A (MAT2A) has received significant interest because of its implication as a synthetic lethal target in methylthioadenosine Phosphorylase (MTAP)-deleted cancers. Here, we report the discovery of a series of 3H-pyrido[1,2-c]pyrimidin-3-one derivatives as novel MAT2A inhibitors. The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.

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