2. Academic Validation
  3. Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1

Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1

  • J Med Chem. 2024 Jun 27;67(12):10306-10320. doi: 10.1021/acs.jmedchem.4c00743.
Mark Sabat 1,  Daniel W Carney 1,  Gloria Hernandez-Torres 1,  Tony S Gibson 1,  Deepika Balakrishna 1,  Hua Zou 1,  Rui Xu 1,  Chien-Hung Chen 1,  Ron de Jong 1,  Douglas R Dougan 1,  Ling Qin 1,  Simone V Bigi-Botterill 1,  Alison Chambers 1,  Joanne Miura 1,  Lucas K Johnson 1,  Jacques Ermolieff 1,  Deidre Johns 1,  Jangir Selimkhanov 1,  Lily Kwok 1,  Kevin DeMent 1,  Chris Proffitt 1,  Phong Vu 1,  Erick A Lindsey 1,  Tony Ivetac 1,  Andy Jennings 1,  Haixia Wang 1,  Padma Manam 1,  Cipriano Santos 1,  Cody Fullenwider 1,  Rohan Manohar 1,  Andrew C Flick 1
Affiliations

Affiliation

  • 1 Gastroenterology Drug Discovery Unit, Takeda Development Center Americas, Inc., 9625 Towne Centre Dr., San Diego, California 92121 United States.
PMID: 38872300 DOI: 10.1021/acs.jmedchem.4c00743
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, in silico 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 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 αvβ1 inhibition.

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