Discovery of N -Acyl Pyrimidine-Biphenyl Small-Molecule PD-L1 Inhibitors that Restore T Cell Function and Suppress Tumor Growth in Breast Cancer
Vidya Jyothi Alli, Teja Nallavolu, Maresha Ramakrishna, Bhumesh Machukuri, Karamtoth Swapnanjali, Swapnil Anil Sule, Baji Baba Shaik, Yogesh Chandra, Ramesh Ummanni, Surender Singh JadavAbstract
The programmed death ligand-1 (PD-L1) is a promising target for cancer immunotherapy; however, no small-molecule inhibitors are approved to date. Herein, we designed and synthesized a series of N-acyl pyrimidine–biphenyl analogues as small-molecule PD-L1 inhibitors. Initial screening identified A6 and A12 as potent PD-L1 binders with EC50 values of 364 nM and 594 nM, respectively, in the luciferase reporter assay. The slightly superior activity of A6 was due to persistent binding with D122 during molecular dynamics. A6 also disrupted PD-1/PD-L1 interaction in an ELISA assay (EC50 = 15.21 μM). Functionally, A6 restored T cell activity, enhanced cytokine secretion, and promoted T cell-mediated tumor cytotoxicity. Importantly, A6 significantly suppressed tumor growth in a syngeneic 4T1 breast cancer model without any systemic toxicity, highlighting its potential to develop pyrimidine-based PD-L1 inhibitors for cancer immunotherapy.