Structure-Based Design of Highly Potent Toll-like Receptor 7/8 Dual Agonists for Cancer Immunotherapy

J Med Chem. 2021 Jun 10;64(11):7507-7532. doi: 10.1021/acs.jmedchem.1c00179. Epub 2021 May 28.

Abstract

Activation of the toll-like receptors 7 and 8 has emerged as a promising strategy for cancer immunotherapy. Herein, we report the design and synthesis of a series of pyrido[3,2-d]pyrimidine-based toll-like receptor 7/8 dual agonists that exhibited potent and near-equivalent agonistic activities toward TLR7 and TLR8. In vitro, compounds 24e and 25a significantly induced the secretion of IFN-α, IFN-γ, TNF-α, IL-1β, IL-12p40, and IP-10 in human peripheral blood mononuclear cell assays. In vivo, compounds 24e, 24m, and 25a significantly suppressed tumor growth in CT26 tumor-bearing mice by remodeling the tumor microenvironment. Additionally, compounds 24e, 24m, and 25a markedly improved the antitumor activity of PD-1/PD-L1 blockade. In particular, compound 24e combined with the anti-PD-L1 antibody led to complete tumor regression. These results demonstrated that TLR7/8 agonists (24e, 24m, and 25a) held great potential as single agents or in combination with PD-1/PD-L1 blockade for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Drug Design*
  • Humans
  • Immunotherapy
  • Interleukin-1beta / metabolism
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Structure-Activity Relationship
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 8 / agonists*
  • Toll-Like Receptor 8 / metabolism
  • Tumor Microenvironment
  • Tumor Necrosis Factor-alpha / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Interleukin-1beta
  • Pyridines
  • Pyrimidines
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Tumor Necrosis Factor-alpha
  • pyrido(3,2-d)pyrimidine