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.