8W30

Crystal structure of alpha-V beta-1 integrin headpiece in complex with TR01225179

This is a non-PDB format compatible entry.

Summary for 8W30

• Entry DOI: 10.2210/pdb8w30/pdb
• Descriptor: Integrin alpha-V heavy chain, Integrin beta-1, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: membrane receptor, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 120599.91

Authors

Qin, L.,Lane, W. (deposition date: 2024-02-21, release date: 2025-01-01)

Primary citation

Sabat, M.,Carney, D.W.,Hernandez-Torres, G.,Gibson, T.S.,Balakrishna, D.,Zou, H.,Xu, R.,Chen, C.H.,de Jong, R.,Dougan, D.R.,Qin, L.,Bigi-Botterill, S.V.,Chambers, A.,Miura, J.,Johnson, L.K.,Ermolieff, J.,Johns, D.,Selimkhanov, J.,Kwok, L.,DeMent, K.,Proffitt, C.,Vu, P.,Lindsey, E.A.,Ivetac, T.,Jennings, A.,Wang, H.,Manam, P.,Santos, C.,Fullenwider, C.,Manohar, R.,Flick, A.C.
Design and Discovery of a Potent and Selective Inhibitor of Integrin alpha v beta 1.
J.Med.Chem., 67:10306-10320, 2024

PubMed Abstract: Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvβ1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvβ1 relative to several other integrin isoforms measured. Azabenzimidazolone demonstrated antifibrotic efficacy in an rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvβ1 inhibition.

PubMed: 38872300
DOI: 10.1021/acs.jmedchem.4c00743

Experimental method

X-RAY DIFFRACTION (2.45 Å)