Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases

  • J Enzyme Inhib Med Chem. 2024 Dec;39(1):2406025. doi: 10.1080/14756366.2024.2406025.
Kai-Cheng Hsu  1  2  3  4 ,  Yun-Yi Huang  1 ,  Jung-Chun Chu  1 ,  Yu-Wen Huang  5 ,  Jing-Lan Hu  6 ,  Tony Eight Lin  2  3 ,  Shih-Chung Yen  7 ,  Jing-Ru Weng  6 ,  Wei-Jan Huang  1  5  8
Affiliations
  • 1. Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 2. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3. Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 4. Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 5. Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 6. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
  • 7. Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China.
  • 8. School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
PMID: 39316378 DOI: 10.1080/14756366.2024.2406025
Abstract

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC Inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 Inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human Cancer cells, induced Apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of Cancer therapeutics.

Keywords
Class IIa histone deacetylases (HDACs); cancer cells; molecular modelling; structure-activity relationship (SAR).
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