8S9H

Crystal structure of monkey TLR7 ectodomain with compound 14

Summary for 8S9H

• Entry DOI: 10.2210/pdb8s9h/pdb
• Descriptor: Toll-like receptor 7, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: toll-like receptor 7, pattern recognition receptor, immune system, agonist
• Biological source: Macaca mulatta (Rhesus monkey)
• Total number of polymer chains: 2
• Total formula weight: 194255.46

Authors

Critton, D.A. (deposition date: 2023-03-28, release date: 2024-02-07, Last modification date: 2024-10-23)

Primary citation

He, L.,Zhang, M.Y.,Cox, M.,Zhang, Q.,Donnell, A.F.,Zhang, Y.,Tarby, C.,Gill, P.,Subbaiah, M.A.M.,Ramar, T.,Reddy, M.,Puttapaka, V.,Li, Y.X.,Sivaprakasam, P.,Critton, D.,Mulligan, D.,Xie, C.,Ramakrishnan, R.,Nagar, J.,Dudhgaonkar, S.,Murtaza, A.,Oderinde, M.S.,Schieven, G.L.,Mathur, A.,Gavai, A.V.,Vite, G.,Gangwar, S.,Poudel, Y.B.
Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.
Acs Med.Chem.Lett., 15:189-196, 2024

PubMed Abstract: Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound , which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound demonstrated excellent pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing in immuno-oncology therapies with immune checkpoint blockade agents.

PubMed: 38352849
DOI: 10.1021/acsmedchemlett.3c00456

Experimental method

X-RAY DIFFRACTION (2.437 Å)