N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression

• Published in: European journal of medicinal chemistry 2020-01, Vol.185, p.111725-111725, Article 111725
• Main Authors: Mehndiratta, Samir, Lin, Mei-Hsiang, Wu, Yi-Wen, Chen, Chun-Han, Wu, Tung-Yun, Chuang, Kuo-Hsiang, Chao, Min-Wu, Chen, Yi-Ying, Pan, Shiow-Lin, Chen, Mei-Chuan, Liou, Jing-Ping
• Format: Article
• Language: English
• Subjects: Anilides - chemical synthesis; Anilides - chemistry; Anilides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - biosynthesis; Cell Proliferation - drug effects; Design multiple ligand; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Drug Screening Assays, Antitumor; Dual inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heat shock protein; Histone deacetylase inhibitors; Histone Deacetylases - metabolism; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Lung cancer; Molecular Structure; Programmed death-ligand 1 (PD-L1); Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111725

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 IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 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. [Display omitted] •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.