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

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

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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