The PI3K signaling pathway is crucial to many aspects of cell growth and survival via its regulation of widely divergent physiological processes that include cell cycle progression, differentiation, transcription, translation and apoptosis. Dysregulation, either through amplification or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. This has prompted intense interest in the development of small molecule modulators of key proteins in this cascade. Structure guided design based on homology modeling was employed to develop series of novel dual PI3K\#945;/mTOR inhibitors. These compounds inhibit the kinase activity of both mTOR complexes. This is demonstrated in a cellular environment through the inhibition of phosphorylation of both S6K and Akt (S473). Extensive SAR studies have shown that subtle differences between these two targets may be exploited to deliver inhibitors with selectivity in either direction. Furthermore, the excellent pharmacokinetic/pharmacodynamic (PK/PD) profile of some of these compounds has meant that sustained shut down of the signaling pathway can be accomplished in vivo as evidenced through the inhibition of S6K and pAkt (S473) by more than 80% for up to 24 h following a single oral dose. Target inhibition has subsequently been shown to result in dose dependant tumor growth inhibition (SB2015, TGI= 96%, 150mg/kg PO QD for 28 days) in mouse xenograft models at dose levels well tolerated. Extensive profiling of these compounds against panels of enzymes and receptors has also shown them to be extremely selective towards mTOR and PI3K.Work is currently in progress to further evaluate the phenotype of inhibitors exhibiting a range of pharmacological profiles against the two targets. The progression of lead candidates towards clinical development is being pursued.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3710.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009