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Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC 50 values in nanomolar range with Compound 20 (HDAC IC 50 = 194 nM; HSP90α IC 50 = 153 nM) and compound 26 (HDAC IC 50 = 360 nM; HSP90α IC 50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future. Image 1 • N -alkyl-hydroxybenzoyl anilide hydroxamates show potent dual inhibition of HDAC and HSP90a. • Lead compounds 20 and 26 induce HSP70 expression and down regulate HSP90 client proteins. • Compounds 20 and 26 displayed their HDAC inhibitory effects due to increased acetylated α-tubulin and histone H3 levels. • Compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells. [ABSTRACT FROM AUTHOR]

• Quinoline – resorcinol hybrid constructs were designed and synthesized. • Compound 11 displayed potent cell growth inhibitory effects against PC-3 cell lines with GI 50 value of 0.14 µM. • The antiproliferative effects of 11 were mediated through Hsp90 chaperone inhibition. • Compound 11 demonstrated apoptosis inducing ability and caused G2M phase cell cycle arrest. • Docking studies revealed key interactions of 11 with amino acid residues of the HSP90 chaperone protein. The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11 , which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined. [ABSTRACT FROM AUTHOR]

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 50 = 4.3 nM) and HSP90a inhibition (IC 50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI 50 = 0.76 μM (lung A549) and GI 50 = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI 50 = 0.37 μM) and lung H1975 cell lines (GI 50 = 0.13 μM) mediated through selective HDAC6 inhibition (IC 50 = 33.3 nM) and HSP90 inhibition (IC 50 = 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. Image 1 • 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. [ABSTRACT FROM AUTHOR]