2. Academic Validation
  3. Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition

Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition

  • Eur J Med Chem. 2023 Dec 15:265:116042. doi: 10.1016/j.ejmech.2023.116042.
Yu-Wei Tseng 1,  Tsung-Jung Yang 1,  Yuan-Ling Hsu 2,  Jyung-Hurng Liu 3,  Yin-Chen Tseng 4,  Tse-Wei Hsu 1,  Yueh Lu 1,  Szu-Hua Pan 5,  Ting-Jen Rachel Cheng 6,  Jim-Min Fang 7
Affiliations

Affiliations

  • 1 Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.
  • 2 Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
  • 3 Graduate Institute of Genomics and Bioinformatics, College of Life Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
  • 4 The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
  • 5 Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, 100, Taiwan; Doctoral Degree Program of Translational Medicine, National Taiwan University, Taipei, 100, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, 100, Taiwan. Electronic address: shpan@ntu.edu.tw.
  • 6 The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. Electronic address: tingjenc@gate.sinica.edu.tw.
  • 7 Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan; The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. Electronic address: jmfang@ntu.edu.tw.
PMID: 38141287 DOI: 10.1016/j.ejmech.2023.116042
Abstract

Dual-targeting Anticancer agents 4-29 are designed by combining the structural features of purine-type microtubule-disrupting compounds and HDAC inhibitors. A library of the conjugate compounds connected by appropriate linkers was synthesized and found to possess HDACs inhibitory activity and render microtubule fragmentation by activating katanin, a microtubule-severing protein. Among various zinc-binding groups, hydroxamic acid shows the highest inhibitory activity of Class I HDACs, which was also reconfirmed by three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore prediction. The purine-hydroxamate conjugates exhibit enhanced cytotoxicity against MDA-MB231 breast Cancer cells, H1975 lung Cancer cells, and various clinical isolated non-small-cell lung Cancer cells with different epidermal growth factor receptor (EGFR) status. Pyridyl substituents could be used to replace the C2 and N9 phenyl moieties in the purine-type scaffold, which can help to improve the solubility under physiological conditions, thus increasing cytotoxicity. In mice treated with the purine-hydroxamate conjugates, the tumor growth rate was significantly reduced without causing toxic effects. Our study demonstrates the potential of the dual-targeting purine-hydroxamate compounds for Cancer monotherapy.

Keywords

Breast cancer; Histidine deacetylase; Hydroxamate; Katanin; Lung cancer; Microtubule; Purine-type conjugate.

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