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 KHSP90a inhibition (IC50 = 46.8 mu M) along with substantial cell growth inhibitory effects with GI(50) = 0.76 mu M (lung A549) and GI(50) = 0.52 mu M (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI(50) = 0.37 mu M) and lung H1975 cell lines (GI(50) = 0.13 mu M) mediated through selective HDAC6 inhibition (IC50 = 33.3 mu M) and HSP90 inhibition (IC50 = 66 mu M). 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 xeno-grafts, 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-gamma treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area. (C) 2020 Published by Elsevier Masson SAS.