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

…, BA Petronella, A Cooke, M Kadalbajoo…

Index: Jin, Meizhong; Petronella, Brenda A.; Cooke, Andy; Kadalbajoo, Mridula; Siu, Kam W.; Kleinberg, Andrew; May, Earl W.; Gokhale, Prafulla C.; Schulz, Ryan; Kahler, Jennifer; Bittner, Mark A.; Foreman, Kenneth; Pachter, Jonathan A.; Wild, Robert; Epstein, David; Mulvihill, Mark J. ACS Medicinal Chemistry Letters, 2013 , vol. 4, # 7 p. 627 - 631

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Citation Number: 7

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 (t 1/2) of> 100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth ...