Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy

  • J Med Chem. 2025 Mar 13;68(5):5426-5454. doi: 10.1021/acs.jmedchem.4c02510.
Zhihao Hu  1 ,  Shuqing Li  1 ,  Haiqi He  2 ,  Wanyi Pan  1 ,  Ting Liu  2 ,  Hailiu Liang  1 ,  Congcong Xu  1 ,  Benyan Lu  1 ,  Chengpeng Tao  1 ,  Zetao Qi  1 ,  Binbin Cheng  3 ,  Ying Hu  4 ,  Feng Jiang  1 ,  Jianjun Chen  2 ,  Xiaopeng Peng  1
Affiliations
  • 1. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Jiangxi Provincial Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou 341000, P. R. China.
  • 2. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3. School of Medicine, Hubei Polytechnic University, Huangshi 435003, China.
  • 4. Department of Gastroenterology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 314000, China.
PMID: 39979078 DOI: 10.1021/acs.jmedchem.4c02510
Abstract

A series of novel PD-L1/HDAC6 dual inhibitors were designed and synthesized, and compound HP29 was identified as the most potent candidate, which demonstrated excellent and selective HDAC6 inhibitory activity (IC50 = 78 nM, SI > 1282), and high anti-PD-1/PD-L1 activity (IC50 = 26.8 nM). Further studies showed that HP29 could bind with high affinity to PD-L1 and HDAC6 protein. Furthermore, HP29 possessed favorable in vivo pharmacokinetic properties, such as decent oral bioavailability (F = 15.3%). Moreover, HP29 exhibited significant in vivo antitumor efficacy in a melanoma tumor model with a greater tumor growth inhibition (TGI) (65.5%) than that of NP19 (43.2%), ACY-1215 (45.6%), and the combination group (53.9%). Mechanistically, the percentages of tumor-infiltrating lymphocytes (TILs) in the HP29-treated tumor tissues were significantly higher than the combination group or PD-L1 inhibitor monotherapy group, suggesting potential synergistic antitumor immune effects. Collectively, HP29 represents a novel PD-L1/HDAC6 dual inhibitor deserving further investigation as a potential Cancer immunomodulating agent.

Products