The mammalian target of rapamycin (mTOR) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. mTOR exists in at least two functional protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). While rapamycin and its analogs (rapalogs) inhibit only mTORC1, ATP‐competitive inhibitors of mTOR target both mTORC1 and mTORC2 and therefore have the potential for improved anticancer efficacy. We have previously reported on the pyrazolopyrimidine series of ATP‐competitive mTOR inhibitors (J. Med. Chem. 2009, 52, 5013 – 5016). We now report that derivatization of the morpholine ring in these inhibitors leads to greatly enhanced mTOR selectivity versus PI3K. Selective mTOR inhibitors have the potential to achieve a higher therapeutic index in the clinic due to better tolerability. Testing these inhibitors in tumor cells and evaluating the most potent analogs in human tumor xenograft models in the nude mouse led to the identification of WYE‐125132, a candidate for clinical development. WYE‐125132 is also selective versus a wide range of other kinases including the closely‐related PIKKs. Detailed structure activity relationships in the pyrazolopyrimidine series will be presented. In conclusion, modification of the morpholine ring of a series of pyrazolopyrimidines leads to analogs with enhanced mTOR selectivity over PI3K and potent efficacy in human tumor xenograft models in the nude mouse.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B145.