This invention presents the crystal structures of the mammalian target of rapamycin (mTOR) and co-crystal structures of its ATP-competitive inhibitors. In doing so, it provides a powerful framework and intellectual property rights for the design and optimization of mTOR inhibitors in drug development. As a research tool, it should be of particular value in supporting the development of enhanced, second-generation therapeutics.
mTOR is a master regulator of cell growth, and most cancers have been found to harbor mutations that inappropriately activate this protein. Therefore, mTOR inhibitors have been the focus of drug discovery for cardiovascular diseases, diabetes, neurological disorders, and many tumors, including breast cancer, gastric cancers, liver cancer, prostate cancer, and renal cancer, among others.
The atomic details of the mTOR ATP-binding site configuration elucidated by this invention will provide robust competitive advantages, such as key information and intellectual property rights, for potential pharmaceutical licensees to develop “tailor-made” new mTOR inhibitors with improved efficacy and safety.
Due to the prior lack of understanding of mTOR structure, the current generation of FDA-approved mTOR inhibitors were mostly developed through the approach of traditional medicinal chemistry, based on the natural compound rapamycin. Memorial Sloan Kettering’s invention enables the design and development of next-gen mTOR inhibitors with enhanced potency and specificity based on the crystal structure of mTOR.
The MSKCC inventors are the first to reveal the detailed crystal structure of the catalytically active mTOR kinase, as well as co-crystal structures of mTOR with specific ATP-binding-site inhibitors, which can greatly facilitate the drug discovery of more potent and selective mTOR inhibitors.
Therapeutic Drug Development
Nikola P. Pavletich, PhD, Program Chair and Laboratory Head, Structural Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering
PCT/US2014/035035 filed April 22, 2014
Yang H et al. (2013) Nature 497:217-223; Alessi D and Kulathu Y (2013) Nature 497:193-194
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