Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics

  • ACS Med Chem Lett. 2013 May 23;4(7):627-31. doi: 10.1021/ml400160a.
Meizhong Jin  1 ,  Brenda A Petronella  1 ,  Andy Cooke  1 ,  Mridula Kadalbajoo  1 ,  Kam W Siu  1 ,  Andrew Kleinberg  1 ,  Earl W May  1 ,  Prafulla C Gokhale  1 ,  Ryan Schulz  1 ,  Jennifer Kahler  1 ,  Mark A Bittner  1 ,  Kenneth Foreman  1 ,  Jonathan A Pachter  1 ,  Robert Wild  1 ,  David Epstein  1 ,  Mark J Mulvihill  1
Affiliations
  • 1. OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
PMID: 24900721 DOI: 10.1021/ml400160a
Abstract

This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity and structure-kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life (t 1/2) of >100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.

Keywords
Insulin-like growth factor-1 receptor (IGF-1R); cancer; slow off-rate; time-dependent inhibition.