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This letter describes a series of smaller Vincristine molecule inhibitors of IGF-1R with special time-dependent binding kinetics and slow off-rates. Framework action and framework kinetic relationships have been elucidated and guided even further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life Brefeldin A protein transport (t(1/2)) of >100 h, compound two demonstrated, significant and extended pp effects in conjunction with tumor growth inhibition the to xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.