1. Academic Validation
  2. Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology

  • ACS Med Chem Lett. 2024 Jan 8;15(2):181-188. doi: 10.1021/acsmedchemlett.3c00455.
Yam B Poudel 1 Liqi He 1 Matthew Cox 1 Qian Zhang 1 Walter L Johnson 1 Qiang Cong 1 Heng Cheng 1 Naidu S Chowdari 1 Christine Tarby 2 Andrew F Donnell 2 Matthais Broekema 2 Daniel P O'Malley 2 Yong Zhang 2 Murugaiah A M Subbaiah 3 Boda Vijay Kumar 3 Lakshumanan Subramani 3 Bei Wang 2 Yi-Xin Li 1 Prasanna Sivaprakasam 2 David Critton 2 Dawn Mulligan 2 Bhupindar Sandhu 2 Chunshan Xie 2 Radha Ramakrishnan 2 Jignesh Nagar 3 Shailesh Dudhgaonkar 3 Martins S Oderinde 2 Anwar Murtaza 2 Gary L Schieven 2 Arvind Mathur 2 Ashvinikumar V Gavai 2 Gregory Vite 2 Sanjeev Gangwar 1
Affiliations

Affiliations

  • 1 Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • 2 Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • 3 The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
Abstract

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

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