Abstract #2014: ATP competitive inhibitors of the mammalian target of rapamycin (mTOR): Design and synthesis of novel, highly selective pyrazolopyrimidines with potent in vivo antitumor activity

Inhibitors of the mammalian target of rapamycin (mTOR), a key regulator of cell growth and proliferation, are clinically proven anticancer agents. Temsirolimus (CCI-779) is approved for use in renal cell carcinoma, and other rapamycin analogs (rapalogs) are in clinical and preclinical development. While mTOR exists as two functionally distinct protein complexes, mTORC1 and mTORC2, the rapalogs effectively inhibit only mTORC1 through allosteric binding at the FRB domain. ATP competitive inhibitors of mTOR bind to both mTORC1 and mTORC2 complexes, leading to more complete and global inhibition of the mTOR pathways, with the potential for broader and more robust anticancer activity. We describe the design, synthesis, and structure activity relationships of ATP competitive, highly selective inhibitors of mTOR with potent in vivo antitumor activity. These analogs have subnanomolar mTOR IC50 values and >1000 fold selectivity versus various isoforms of PI3K and related enzymes in the PIKK family. Molecular modeling identified key hydrogen bonding interactions between the inhibitors and mTOR responsible for enhanced potency and selectivity. Biomarker inhibition in vitro in cancer cell lines and in vivo in tumor xenograft models showed selective mTOR inhibition, as evidenced by suppression of phosphorylation of the mTOR substrate AKT Ser-473, without affecting the phosphorylation of AKT Ser-308 by PI3Kalpha. Potent suppression of tumor growth was achieved in tumor xenograft models by both oral and intravenous dosing regimens. These results highlight specific kinase inhibitors of mTOR as new and promising anticancer therapy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2014.