Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody-Drug Conjugate Payloads

  • J Med Chem. 2024 Sep 12;67(17):15756-15779. doi: 10.1021/acs.jmedchem.4c01384.
Akash M Patel  1 ,  Aarron Willingham  2 ,  Alan C Cheng  3 ,  Daniela Tomazela  2 ,  Eddie Bowman  4 ,  Esther Kofman  2 ,  Fan Zhang  2 ,  Jianming Bao  5 ,  Jillian R Sanzone  5 ,  Jonathan W Choy  4 ,  John A Flygare  1 ,  Jin-Hwan Han  4 ,  Komal Pradhan  4 ,  Madeleine Kieffer  1 ,  Natalia Chernyak  1 ,  Peyman Akbari  4 ,  Ping Liu  5 ,  Rimsha Mehmood  3 ,  Saraswathi Naravula  2 ,  Scott A Hollingsworth  3 ,  Bhagyashree Bhagwat  2 ,  Simon B Lang  1 ,  W Michael Seganish  1
Affiliations
  • 1. Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States.
  • 2. Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States.
  • 3. Modeling and Informatics, Merck & Co. Inc., South San Francisco, California 94080, United States.
  • 4. Discovery Oncology, Merck & Co. Inc., South San Francisco, California 94080, United States.
  • 5. External Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States.
PMID: 39172064 DOI: 10.1021/acs.jmedchem.4c01384
Abstract

Toll-like receptors 7 and 8 are involved in modulating the adaptive and innate immune responses, and their activation has shown promise as a therapeutic strategy in the field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result in poor tolerance, combination therapies and targeted delivery through antibody-drug conjugates (ADCs) can help mitigate adverse effects. Described herein is the identification of a novel and potent series of pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity. Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.

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