2. Academic Validation
  3. Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics

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

Affiliation

  • 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.

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