The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation and plays a gate keeper role in the control of cell cycle progression and mediates mitogenic signals from PI3K/AKT through to the downstream target S6K1 and 4E-BP1 and to Ser 473 on AKT. In cancer, mTOR is frequently hyper-activated and is a clinically validated target of therapy. In our high-through-put screening campaign, we have identified several ATP-competitive mTOR inhibitors with different chemical structures. The initial evaluation revealed that pyrazolo[1,5-a]pyrimidin-7-amine derivative (cpd-1  ) has good PI3Ka selectivity and was selected as the major focus as selective mTOR inhibitors may be better tolerated. With the aide of computational modeling, the subsequent hit to lead optimization efforts improved the both enzyme and cellular potency. Cpd-2 selected for in vivo study demonstrated good efficacy in cancer Xenograft models in nude mice. The syntheses and structure-activity relationship of the representative compounds will also be presented.

Discovery of pyrazolo[1,5-a]pyrimidin-7-amine derivatives as mTOR kinase domain inhibitors: Hit to lead optimization

248th National Meeting (2014)

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