2. Academic Validation
  3. N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment

N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment

  • J Med Chem. 2022 Feb 10;65(3):2208-2224. doi: 10.1021/acs.jmedchem.1c01726.
Samir Mehndiratta 1 2 3,  Bin Qian 1,  Jian-Ying Chuang 3,  Jing-Ping Liou 2 4,  Jean C Shih 1 5 6 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, United States.
  • 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 3 The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
  • 4 TMU Research Center of Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
  • 5 Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.
  • 6 USC-Taiwan Center for Translational Research, Los Angeles, California 90089, United States.
PMID: 35005974 DOI: 10.1021/acs.jmedchem.1c01726
Abstract

Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine Oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 μM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.

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