2. Academic Validation
  3. Discovery of Pyrrole-imidazole Polyamides as PD-L1 Expression Inhibitors and Their Anticancer Activity via Immune and Nonimmune Pathways

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

  • J Med Chem. 2021 May 13;64(9):6021-6036. doi: 10.1021/acs.jmedchem.1c00120.
Ming Wang 1 2,  Xudong Ma 1 2,  Kang Zhou 1 2,  Huijuan Mao 1 2,  Jiachun Liu 1 2,  Xuqiong Xiong 1 2,  Xiaoyin Zhao 1 2,  Suresh Narva 1 2,  Yoshimasa Tanaka 3,  Yanling Wu 4,  Chuanxin Guo 5,  Hiroshi Sugiyama 5,  Wen Zhang 1 2
Affiliations

Affiliations

  • 1 Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2 Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China.
  • 3 Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • 4 Lab of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China.
  • 5 Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
PMID: 33949196 DOI: 10.1021/acs.jmedchem.1c00120
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.

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