8w30
Crystal structure of alpha-V beta-1 integrin headpiece in complex with TR01225179
Structural highlights
FunctionITB1_HUMAN Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. Isoform beta-1B interferes with isoform beta-1A resulting in a dominant negative effect on cell adhesion and migration (in vitro). In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. When associated with alpha-7/beta-1 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and GNB2L1/RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis.[1] [2] [3] Publication Abstract from PubMedSelective inhibition of the RGD (Arg-Gly-Asp) integrin alphavbeta1 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, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for alphavbeta1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective alphavbeta1 inhibition. Design and Discovery of a Potent and Selective Inhibitor of Integrin alphavbeta1.,Sabat M, Carney DW, Hernandez-Torres G, Gibson TS, Balakrishna D, Zou H, Xu R, Chen CH, de Jong R, Dougan DR, Qin L, Bigi-Botterill SV, Chambers A, Miura J, Johnson LK, Ermolieff J, Johns D, Selimkhanov J, Kwok L, DeMent K, Proffitt C, Vu P, Lindsey EA, Ivetac T, Jennings A, Wang H, Manam P, Santos C, Fullenwider C, Manohar R, Flick AC J Med Chem. 2024 Jun 27;67(12):10306-10320. doi: 10.1021/acs.jmedchem.4c00743. , Epub 2024 Jun 13. PMID:38872300[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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