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.

Automated summary

A small-molecule Py-Im polyamide was designed and synthesized to competitively bind to the same DNA region as STAT3 in the PD-L1 promoter, downregulating PD-L1 expression and inducing apoptosis in tumor cells through Akt/caspase-3 pathway inhibition. Additionally, these polyamides enhanced T-cell-mediated killing of tumor cells and showed potential as PD-L1 gene-targeting antitumor drugs through immune and nonimmune pathways.