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Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.
Poudel, Yam B; He, Liqi; Cox, Matthew; Zhang, Qian; Johnson, Walter L; Cong, Qiang; Cheng, Heng; Chowdari, Naidu S; Tarby, Christine; Donnell, Andrew F; Broekema, Matthais; O'Malley, Daniel P; Zhang, Yong; A M Subbaiah, Murugaiah; Kumar, Boda Vijay; Subramani, Lakshumanan; Wang, Bei; Li, Yi-Xin; Sivaprakasam, Prasanna; Critton, David; Mulligan, Dawn; Sandhu, Bhupindar; Xie, Chunshan; Ramakrishnan, Radha; Nagar, Jignesh; Dudhgaonkar, Shailesh; Oderinde, Martins S; Murtaza, Anwar; Schieven, Gary L; Mathur, Arvind; Gavai, Ashvinikumar V; Vite, Gregory; Gangwar, Sanjeev.
Affiliation
  • Poudel YB; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • He L; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Cox M; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Zhang Q; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Johnson WL; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Cong Q; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Cheng H; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Chowdari NS; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Tarby C; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Donnell AF; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Broekema M; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • O'Malley DP; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Zhang Y; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • A M Subbaiah M; The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
  • Kumar BV; The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
  • Subramani L; The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
  • Wang B; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Li YX; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • Sivaprakasam P; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Critton D; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Mulligan D; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Sandhu B; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Xie C; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Ramakrishnan R; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Nagar J; The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
  • Dudhgaonkar S; The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
  • Oderinde MS; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Murtaza A; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Schieven GL; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Mathur A; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Gavai AV; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Vite G; Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • Gangwar S; Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
ACS Med Chem Lett ; 15(2): 181-188, 2024 Feb 08.
Article in En | MEDLINE | ID: mdl-38352830
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-1ß, 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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Full text: 1 Database: MEDLINE Language: En Year: 2024 Type: Article
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Full text: 1 Database: MEDLINE Language: En Year: 2024 Type: Article