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
  • 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.
PMID: 38352830 DOI: 10.1021/acsmedchemlett.3c00455
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.