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.
摘要：
设计了靶向PD-L1/PARP7的双功能缀合物，合成，并进行了首次评估。化合物B3和C6显示出对PD-1/PD-L1相互作用的有效活性(IC50=0.426和0.342μM,分别）和PARP7（IC50=2.50和7.05nM，分别)。它们还显示出与hPD-L1的优异结合亲和力,比hPD-1好大约100-200倍。两种化合物都恢复了T细胞功能，导致IFN-γ分泌增加。在共培养试验中，B3和C6以浓度依赖性方式增强JurkatT细胞对MDA-MB-231细胞的杀伤活性。此外，B3和C6在黑色素瘤B16-F10肿瘤小鼠模型中显示出显著的体内抗肿瘤功效，在25mg/kg的剂量下，比BMS-1（PD-L1抑制剂）和RBN-2397（PARP7i临床候选药物）好5.3倍以上，没有明显的副作用。这些结果为开发用于潜在抗癌治疗的双功能缀合物提供了有价值的见解和理解。
