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Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2020 Mar 15; Vol. 190, pp. 112086. Date of Electronic Publication: 2020 Jan 23. - Publication Year :
- 2020
-
Abstract
- 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 (IC <subscript>50</subscript>  = 4.3 nM) and HSP90a inhibition (IC <subscript>50</subscript>  = 46.8 nM) along with substantial cell growth inhibitory effects with GI <subscript>50</subscript>  = 0.76 μM (lung A549) and GI <subscript>50</subscript>  = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI <subscript>50</subscript>  = 0.37 μM) and lung H1975 cell lines (GI <subscript>50</subscript>  = 0.13 μM) mediated through selective HDAC6 inhibition (IC <subscript>50</subscript>  = 33.3 nM) and HSP90 inhibition (IC <subscript>50</subscript>  = 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020. Published by Elsevier Masson SAS.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents metabolism
Apoptosis drug effects
Carcinoma, Non-Small-Cell Lung drug therapy
Catalytic Domain
Cell Line, Tumor
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
HSP90 Heat-Shock Proteins chemistry
HSP90 Heat-Shock Proteins metabolism
Histone Deacetylase 6 chemistry
Histone Deacetylase 6 metabolism
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors metabolism
Humans
Hydroxamic Acids chemical synthesis
Hydroxamic Acids metabolism
Isoindoles chemical synthesis
Isoindoles metabolism
Male
Mice, Inbred BALB C
Molecular Docking Simulation
Protein Binding
Xenograft Model Antitumor Assays
Antineoplastic Agents therapeutic use
HSP90 Heat-Shock Proteins antagonists & inhibitors
Histone Deacetylase Inhibitors therapeutic use
Hydroxamic Acids therapeutic use
Isoindoles therapeutic use
Lung Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 190
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32058238
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112086