{Reference Type}: Journal Article
{Title}: Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment.
{Author}: Gao Y;Duan JL;Wang CC;Yuan Y;Zhang P;Wang ZH;Sun B;Zhou J;Du X;Dang X;Bai RT;Zhang H;Xie T;Ye XY;
{Journal}: J Med Chem
{Volume}: 67
{Issue}: 13
{Year}: 2024 Jul 11
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.4c00296
{Abstract}: Bifunctional conjugates targeting PD-L1/PARP7 were designed, synthesized, and evaluated for the first time. Compounds B3 and C6 showed potent activity against PD-1/PD-L1 interaction (IC50 = 0.426 and 0.342 μM, respectively) and PARP7 (IC50 = 2.50 and 7.05 nM, respectively). They also displayed excellent binding affinity with hPD-L1, approximately 100-200-fold better than that of hPD-1. Both compounds restored T-cell function, leading to the increase of IFN-γ secretion. In the coculture assay, B3 and C6 enhanced the killing activity of MDA-MB-231 cells by Jurkat T cells in a concentration-dependent manner. Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential anticancer therapy.