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Publication Abstract from PubMed

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-1beta, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNalpha and TNFalpha 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.

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.,Poudel YB, He L, Cox M, Zhang Q, Johnson WL, Cong Q, Cheng H, Chowdari NS, Tarby C, Donnell AF, Broekema M, O'Malley DP, Zhang Y, A M Subbaiah M, Kumar BV, Subramani L, Wang B, Li YX, Sivaprakasam P, Critton D, Mulligan D, Sandhu B, Xie C, Ramakrishnan R, Nagar J, Dudhgaonkar S, Oderinde MS, Murtaza A, Schieven GL, Mathur A, Gavai AV, Vite G, Gangwar S ACS Med Chem Lett. 2024 Jan 8;15(2):181-188. doi: 10.1021/acsmedchemlett.3c00455. , eCollection 2024 Feb 8. PMID:38352830^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.