1. Discovery of Pyrrole-imidazole Polyamides as PD-L1 Expression Inhibitors and Their Anticancer Activity via Immune and Nonimmune Pathways
- Author
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Huijuan Mao, Suresh Narva, Xiaoyin Zhao, Yoshimasa Tanaka, Chuanxin Guo, Xuqiong Xiong, Wang Ming, Xudong Ma, Kang Zhou, Wen Zhang, Yanling Wu, Jiachun Liu, and Hiroshi Sugiyama
- Subjects
STAT3 Transcription Factor ,medicine.drug_class ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,Monoclonal antibody ,01 natural sciences ,B7-H1 Antigen ,03 medical and health sciences ,Immune system ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Pyrroles ,Binding site ,STAT3 ,Protein kinase B ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Imidazoles ,Immunity ,Cell migration ,0104 chemical sciences ,Nylons ,010404 medicinal & biomolecular chemistry ,Drug Design ,biology.protein ,Cancer research ,Molecular Medicine - Abstract
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.
- Published
- 2021