Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo
| Autor: | Mei Hsiang Lin, Mei Chuan Chen, Tung Yun Wu, Kai Cheng Hsu, Kunal Nepali, Tony Eight Lin, Min Wu Chao, Han Li Huang, Shiow Lin Pan, Kuo Hsiang Chuang, Chun Han Chen, Jing Ping Liou, Mei Jung Lai, Ritu Ojha, Chao Di Chang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Lung Neoplasms Afatinib Antineoplastic Agents Apoptosis Isoindoles Histone Deacetylase 6 Hydroxamic Acids 01 natural sciences 03 medical and health sciences chemistry.chemical_compound In vivo Carcinoma Non-Small-Cell Lung Catalytic Domain Cell Line Tumor Drug Discovery medicine Animals Humans HSP90 Heat-Shock Proteins Lung cancer 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences Mice Inbred BALB C biology 010405 organic chemistry Cell growth Organic Chemistry General Medicine Isoindoline HDAC6 medicine.disease Hsp90 Xenograft Model Antitumor Assays In vitro 0104 chemical sciences Histone Deacetylase Inhibitors Molecular Docking Simulation chemistry Cancer research biology.protein Drug Screening Assays Antitumor medicine.drug Protein Binding |
| Zdroj: | European journal of medicinal chemistry. 190 |
| ISSN: | 1768-3254 |
| Popis: | This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC50 = 4.3 nM) and HSP90a inhibition (IC50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI50 = 0.76 μM (lung A549) and GI50 = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI50 = 0.37 μM) and lung H1975 cell lines (GI50 = 0.13 μM) mediated through selective HDAC6 inhibition (IC50 = 33.3 nM) and HSP90 inhibition (IC50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area. |
| Databáze: | OpenAIRE |
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