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

Ritu Ojha; Han-Li Huang; Wei-Chun HuangFu; Yi-Wen Wu; Kunal Nepali; Mei-Jung Lai; Chih-Jou Su; Ting-Yi Sung; Yi-Lin Chen; Shiow-Lin Pan; Jing-Ping Liou

doi:10.1016/j.ejmech.2018.03.006

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. Epub 2018 Mar 5.

Authors

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
HSP90 Heat-Shock Proteins
Histone Deacetylase Inhibitors
Hydroxamic Acids
Indoles
Histone Deacetylases