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

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

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.

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