학술논문
Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.
Document Type
Academic Journal
Author
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.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1948-5875
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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)