2. Academic Validation
  3. Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an in Silico Approach Assisted with the Hole-Electron Analysis

Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an in Silico Approach Assisted with the Hole-Electron Analysis

  • J Med Chem. 2024 Jan 11;67(1):543-554. doi: 10.1021/acs.jmedchem.3c01770.
Huan He 1 2,  Ziwei Wang 1 2,  Xueke Peng 3,  Luolong Qing 1 2,  Yu Zhang 1 2,  Shaojuan Fu 1,  Juan Xu 4,  Yuanyuan Li 5,  Silong Zhang 1
Affiliations

Affiliations

  • 1 Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), 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 Guiyang Healthcare Vocational University, Guiyang 550081, P. R. China.
  • 4 College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi 435003, P. R. China.
  • 5 School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, P. R. China.
PMID: 38166392 DOI: 10.1021/acs.jmedchem.3c01770
Abstract

Small molecules capable of modulating methionine adenosyltransferase 2A (MAT2A) are of significant interest in precise Cancer therapeutics. Herein, we raised the hole-electron Coulombic attraction as a reliable molecular descriptor for predicting the reactive oxygen generation capacity of MAT2A inhibitors, based on which we discovered compound H3 as a sonically activated degrader of MAT2A. Upon sonication, H3 can generate Reactive Oxygen Species to specifically degrade cellular MAT2A via rapid oxidative reactions. Combination of H3 and sonication induced 87% MAT2A depletion in human colon Cancer cells, thus elevating its antiproliferation effects by 8-folds. In vivo, H3 had a favorable pharmacokinetic profile (bioavailability = 77%) and ADME properties. Owing to the MAT2A degradation merits, H3 at a dosage of 10 mg/kg induced 31% tumor regression in xenograft colon tumor models. The significantly boosted antitumor potency can potentially alleviate the toxicity of high-dose MAT2A inhibitors to normal cells and tissues, especially to the liver.

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