Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma

Xiaopeng Peng; Ziwen Yu; Goverdhan Surineni; Bulian Deng; Meizhu Zhang; Chuan Li; Zhiqiang Sun; Wanyi Pan; Yao Liu; Shenglan Liu; Bin Yu; Jianjun Chen

doi:10.1080/14756366.2023.2201408

Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2201408. doi: 10.1080/14756366.2023.2201408.

Authors

Xiaopeng Peng^{1

2}, Ziwen Yu^{1

2}, Goverdhan Surineni^{1

2}, Bulian Deng^{1

2}, Meizhu Zhang^{1

2}, Chuan Li^{1

2}, Zhiqiang Sun^{1

2}, Wanyi Pan^{1

2}, Yao Liu³, Shenglan Liu^{1

2}, Bin Yu⁴, Jianjun Chen^{1

2}

Affiliations

¹ College of Pharmacy, Gannan Medical University, Ganzhou, China.
² School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, China.
³ Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China.
⁴ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.

Abstract

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC₅₀ = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC₅₀ of 7.37-21.84 μM against four cancer cell lines, comparable to that of tubastatin A (average IC₅₀ = 6.10 μM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8⁺ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.

Keywords: HDAC6; anticancer activity; antitumor immunity; inhibitor; tubastatin A.

MeSH terms

CD8-Positive T-Lymphocytes* / metabolism
Cell Line, Tumor
Cell Proliferation
Histone Deacetylase 6 / antagonists & inhibitors
Histone Deacetylase Inhibitors* / pharmacology
Humans
Melanoma* / drug therapy

Substances

HDAC6 protein, human
Histone Deacetylase 6
Histone Deacetylase Inhibitors
tubastatin A

Grants and funding

This work was supported by the National Natural Science Foundation of China (82260676); the Science and Technology Projects of Ganzhou (2021-45-4), the Start-Up Foundation of Gannan Medical University (No. QD202144-2067) to PX; the National Natural Science Foundation of China (82003801) to LS; the National Natural Science Foundation of China (82173668), Thousand Youth Talents Program (C1080092) from the Organization Department of the CPC Central Committee and International Science and Technology Cooperation Projects of Guangdong Province (G819310411) to CJ; and the National Natural Science Foundation of China (82003598) to LY.