8TTZ

Crystal structure of monkey TLR7 ectodomain with compound 20

Summary for 8TTZ

• Entry DOI: 10.2210/pdb8ttz/pdb
• Descriptor: Toll-like receptor 7, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: toll-like receptor 7, immune system
• Biological source: Macaca mulatta (Rhesus monkey)
• Total number of polymer chains: 2
• Total formula weight: 195710.05

Authors

Critton, D.A. (deposition date: 2023-08-15, release date: 2024-02-07, Last modification date: 2024-10-16)

Primary citation

Poudel, Y.B.,He, L.,Cox, M.,Zhang, Q.,Johnson, W.L.,Cong, Q.,Cheng, H.,Chowdari, N.S.,Tarby, C.,Donnell, A.F.,Broekema, M.,O'Malley, D.P.,Zhang, Y.,A M Subbaiah, M.,Kumar, B.V.,Subramani, L.,Wang, B.,Li, Y.X.,Sivaprakasam, P.,Critton, D.,Mulligan, D.,Sandhu, B.,Xie, C.,Ramakrishnan, R.,Nagar, J.,Dudhgaonkar, S.,Oderinde, M.S.,Murtaza, A.,Schieven, G.L.,Mathur, A.,Gavai, A.V.,Vite, G.,Gangwar, S.
Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.
Acs Med.Chem.Lett., 15:181-188, 2024

PubMed Abstract: We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. , 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.

PubMed: 38352830
DOI: 10.1021/acsmedchemlett.3c00455

Experimental method

X-RAY DIFFRACTION (3.14 Å)