Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics.
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ABSTRACT:
SUBMITTER: Jin M
PROVIDER: S-EPMC4027544 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
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Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics.
Jin Meizhong M Petronella Brenda A BA Cooke Andy A Kadalbajoo Mridula M Siu Kam W KW Kleinberg Andrew A May Earl W EW Gokhale Prafulla C PC Schulz Ryan R Kahler Jennifer J Bittner Mark A MA Foreman Kenneth K Pachter Jonathan A JA Wild Robert R Epstein David D Mulvihill Mark J MJ
ACS medicinal chemistry letters 20130523 7
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 intermitten ...[more]
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