2. Academic Validation
  3. 1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC

1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC

  • Eur J Med Chem. 2018 Apr 25:150:667-677. doi: 10.1016/j.ejmech.2018.03.006.
Ritu Ojha 1,  Han-Li Huang 2,  Wei-Chun HuangFu 3,  Yi-Wen Wu 3,  Kunal Nepali 1,  Mei-Jung Lai 4,  Chih-Jou Su 3,  Ting-Yi Sung 5,  Yi-Lin Chen 3,  Shiow-Lin Pan 6,  Jing-Ping Liou 7
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 2 TMU Biomedical Commercialization Center, Taipei, Taiwan.
  • 3 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 4 Center for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 6 TMU Biomedical Commercialization Center, Taipei, Taiwan; The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Biomedical Commercialization Center, Taipei, Taiwan; Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 29567459 DOI: 10.1016/j.ejmech.2018.03.006
Abstract

A series of 1-aroylindoline-hydroxamic acids have been synthesized in the present study. The results of the biological evaluation led to the identification of compound 12 as dual HDAC6/HSP90 Inhibitor. Compound 12 displayed striking inhibitory effects towards the HDAC6 isoform and HSP 90 protein with IC50 values of 1.15 nM (HDAC6) and 46.3 nM (HSP90). Compound 12 also exhibited 113, 139 and 246 fold higher selectivity for HDAC6 over HDAC 1, HDAC 3 and HDAC 8 isoforms and was endowed with significant cytotoxic effects with GI50 values ranging 1.04-1.61 μM against lung A549, colorectal HCT116, leukemia HL60, and EGFR T790M mutant lung H1975 cell lines. Another interesting finding of the study was substantial cytotoxic effects of compounds particularly against lung H1975 (NSCLC) cell lines with IC50 = 0.26 μM which may be mediated through HSP90 inhibition. Compound 8 as such was devoid of HDAC inhibitory activity.

Keywords

Cancer; Heat shock protein; Histone deacetylase inhibitors; Indoline.

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