Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo

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. Compound 17 downregulated PD-L1 expression in INF-γ treated H1975 lung cancer cells. Compound 17 in combination with afatinib enhanced antitumor efficacy. [Display omitted] •1-Aroylisoindoline-hydroxamic acids as dual HDAC6/HSP90 inhibitors have been synthesized.•Compound 17 displays potent inhibition of HDAC6 isoform and HSP90a inhibition.•Compound 17 induced suppression of tumor growth in human H1975 xenografts.•Compound 17 downregulated PD-L1 expression in INF-γ treated H1975 lung cancer cells.•Compound 17 in combination with T cell immunotherapy might be worth investigating for treatment of cancer.