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Discovery of Novel Insulin-Like Growth Factor-1 Receptor Inhibitors with Unique Time-Dependent Binding Kinetics
- Source :
- ACS Medicinal Chemistry Letters. 4:627-631
- Publication Year :
- 2013
- Publisher :
- American Chemical Society (ACS), 2013.
-
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 (t1/2) 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.
Details
- ISSN :
- 19485875
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- ACS Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....71d0beeac5e7bcb9257a057fecc19be4