Discovery of Novel Insulin-Like Growth Factor‑1 Receptor Inhibitors with Unique Time-Dependent Binding Kinetics

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 <b>2</b>. With an IGF-1R dissociative half-life (<i>t</i>_1/2) of >100 h, compound <b>2</b> 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