Rational design of synthetically tractable HDAC6/HSP90 dual inhibitors to destroy immune-suppressive tumor microenvironment

• Published in: Journal of advanced research 2023-04, Vol.46, p.159-171
• Main Authors: Wu, Tung-Yun, Chen, Michael, Chen, I-Chung, Chen, Yi-Jou, Chen, Che-Yi, Wang, Chang-Hung, Cheng, Jing-Jy, Nepali, Kunal, Chuang, Kuo-Hsiang, Liou, Jing-Ping
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Drug design; HDAC6/HSP90 dual inhibitor; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; HSP90 Heat-Shock Proteins - metabolism; Immunosensitizer; Original; Tumor Microenvironment
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2022.06.009

A series of dual selective HDAC6/HSP90 inhibitors, rationally designed via a hybrid scaffold construction approach, effectively killed cancer cells, down-regulated immune checkpoints and systemic immune suppressors, and enhanced T cell anti-tumor activity. The HDAC6/HSP90 dual inhibitors work as both anti-cancer agents and immunosensitizers which can overcome the immunosuppressive tumor microenvironment, bringing a new perspective of chemoimmunotherapy into solid tumor treatment. [Display omitted] •Compound 17 (C.17) is a potent HDAC6/HSP90 dual inhibitor.•C.17 identified as an anti-cancer agent reversing harsh tumor microenvironment.•C.17 reduces inhibitory proteins (PD-L1, IDO) in the tumor region.•Systemic regulatory T cells downregulated by C.17 via suppressing serum TGF-β.•C.17 exhibits low toxicity to immune cells and normal cells.•Combining C.17 with anit-PD1 antibody achieves synergistic tumor destruction. The tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability. We propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic agent that does not only kill tumor cells but also destroys the tumor microenvironment and enhances anti-cancer immunity. A hybrid scaffold construction approach was leveraged to furnish a series of rationally designed resorcinol-based hydroxamates as dual selective HDAC6/HSP90 inhibitors. The drug design campaign commenced with a fragment recruitment process to pinpoint validated structural units to inhibit HDAC6 and HSP90, followed by their installation in flexible HDAC inhibitory templates via an efficient and facile multistep synthetic route. Subsequent evaluations identified a strikingly potent selective HDAC6/HSP90 dual inhibitor (compound 17) via molecular and biological analysis in vitro and in vivo. Compound 17 exhibited not only direct cytotoxicity to cancer cells but also downregulated immune checkpoints (PD-L1 and IDO) expression in tumors via the inhibition of STAT1 pathway and degradation of oncogene proteins (Src, AKT, Rb, and FAK), leading to in vivo tumor growth inhibition. These multiple effects enabled the effector T cells to largely infiltrate into the tumor region and release granzyme B to kill cancer cells. In addition, compound 17 also decreased TGF-β secretion from normal cells, resulting in the systemic re