Yam B Poudel, Liqi He, Matthew Cox, Qian Zhang, Walter L Johnson, Qiang Cong, Heng Cheng, Naidu S Chowdari, Christine Tarby, Andrew F Donnell, Matthais Broekema, Daniel P O'Malley, Yong Zhang, Murugaiah A M Subbaiah, Boda Vijay Kumar, Lakshumanan Subramani, Bei Wang, Yi-Xin Li, Prasanna Sivaprakasam, David Critton, Dawn Mulligan, Bhupindar Sandhu, Chunshan Xie, Radha Ramakrishnan, Jignesh Nagar, Shailesh Dudhgaonkar, Martins S Oderinde, Anwar Murtaza, Gary L Schieven, Arvind Mathur, Ashvinikumar V Gavai, Gregory Vite, Sanjeev Gangwar
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...
February 8, 2024: ACS Medicinal Chemistry Letters