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Discovery and Crystallography Study of Novel Oxadiazole Analogs as Small Molecule PD-1/PD-L1 inhibitors
Structural highlights
FunctionPD1L1_HUMAN Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production.[1] [2] Publication Abstract from PubMedCurrent 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 IC(50) of 16.7 nM, 3.2-fold better than the lead BMS-202 (IC(50) = 53.6 nM). The X-ray crystal structure of LP23 in complex with PD-L1 was solved at a resolution of 2.6 A, 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. Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents.,Liu J, Cheng Y, Yuan L, Liu T, Ruan Y, Ren Y, Li L, Jiang S, Xiao Y, Chen J J Med Chem. 2023 Sep 28;66(18):13172-13188. doi: 10.1021/acs.jmedchem.3c01141. , Epub 2023 Sep 6. PMID:37674362[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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