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Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy
- Source :
- Journal of Medicinal Chemistry; June 2024, Vol. 67 Issue: 11 p9431-9446, 16p
- Publication Year :
- 2024
-
Abstract
- Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39demonstrates excellent brain exposure with a Kpuuof 0.64 in rats.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Volume :
- 67
- Issue :
- 11
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs66517849
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00552