Discovery of Pyrrole-imidazole Polyamides as PD-L1 Expression Inhibitors and Their Anticancer Activity via Immune and Nonimmune Pathways

In recent years, PD-1 immune checkpoint inhibitors based on monoclonal antibodies have revolutionized cancer therapy, but there still exist unresolved issues, such as the high cost, the relatively low response rates, and so on, compared with small-molecule drugs. Herein a type of pyrrole-imidazole (Py-Im) polyamide as a small-molecule DNA binder was designed and synthesized, which could competitively bind to the same double-stranded DNA stretch in the PD-L1 promoter region as the STAT3 binding site and thus downregulate PD-L1 expression. It was demonstrated that the Py-Im polyamides directly caused apoptosis in tumor cells and retarded cell migration in the absence of T cells through inhibiting the Akt/caspase-3 pathway. Also, in a coculture system, they enhanced the T-cell-mediated killing of tumor cells by the reversal of immune escape. Because such polyamides induced antitumor effects via both immune and nonimmune pathways, they could be further developed as promising PD-L1 gene-targeting antitumor drugs.

近年来，基于单克隆抗体的PD-1免疫检查点抑制剂已彻底革新了癌症治疗领域，但与小分子药物相比，其仍存在高成本、应答率相对较低等尚未解决的问题。本文中，研究人员设计并合成了一种作为小分子DNA结合剂的吡咯-咪唑（pyrrole-imidazole, Py-Im）聚酰胺，该物质可竞争性结合PD-L1启动子区域内与STAT3结合位点相同的双链DNA区段，进而下调PD-L1的表达。研究证实，这类Py-Im聚酰胺可通过抑制Akt/半胱天冬酶-3（caspase-3）通路，在缺乏T细胞的情况下直接诱导肿瘤细胞凋亡并延缓细胞迁移。此外，在共培养体系中，这类聚酰胺可通过逆转免疫逃逸，增强T细胞介导的肿瘤细胞杀伤作用。由于这类聚酰胺可通过免疫与非免疫双重通路发挥抗肿瘤作用，因此有望作为靶向PD-L1基因的抗肿瘤候选药物进一步开发。