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
  • 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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