Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents

  • J Med Chem. 2023 Sep 28;66(18):13172-13188. doi: 10.1021/acs.jmedchem.3c01141.
Jin Liu  1  2 ,  Yao Cheng  3  4 ,  Lin Yuan  1 ,  Ting Liu  1 ,  Yong Ruan  1 ,  Yichang Ren  1 ,  Ling Li  1 ,  Sheng Jiang  5 ,  Yibei Xiao  3  4 ,  Jianjun Chen  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • 2. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 3. State Key Laboratory of Natural Medicines and Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 4. Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
  • 5. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 37674362 DOI: 10.1021/acs.jmedchem.3c01141
Abstract

Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound LP23 exhibited the most potent PD-L1 inhibitory activity with an IC50 of 16.7 nM, 3.2-fold better than the lead BMS-202 (IC50 = 53.6 nM). The X-ray crystal structure of LP23 in complex with PD-L1 was solved at a resolution of 2.6 Å, which further confirmed the high binding affinity of LP23 to PD-L1. In the HepG2/Jurkat T cell co-culture model, LP23 effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, LP23 showed excellent in vivo antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, LP23 represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.

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