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ACS Med Chem Lett. 2013 May 23;4(7):627-31. doi: 10.1021/ml400160a. eCollection 2013 Jul 11.

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

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OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.


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.


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

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