Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofura n-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

作者：Tsou Hwei Ru^*; MacEwan Gloria; Birnberg Gary; Grosu George; Bursavich Matthew G; Bard Joel; Brooijmans Natasja; Toral Barza Lourdes; Hollander Irwin; Mansour Tarek S; Ayral Kaloustian Semiramis; Yu Ker

来源：Bioorganic & Medicinal Chemistry Letters, 2010, 20(7): 2321-2325.

DOI：10.1016/j.bmcl.2010.01.135

• mTOR
• Kinase inhibitors
• Anticancer agent
• Phosphoinositide-3-kinase
• Serine/threonine kinase

Wediscovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3K alpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3K gamma revealed the key hydrogen bonding interactions.

• 出版日期2010-4-1