Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR

• Published in: Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (20), p.5898-5901
• Main Authors: Menear, Keith A., Gomez, Sylvie, Malagu, Karine, Bailey, Christine, Blackburn, Kristel, Cockcroft, Xiao-Ling, Ewen, Sally, Fundo, Alexandra, Gall, Armelle Le, Hermann, Gesine, Sebastian, Luisa, Sunose, Mihiro, Presnot, Thomas, Torode, Eleanor, Hickson, Ian, Martin, Niall M.B., Smith, Graeme C.M., Pike, Kurt G.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; General aspects; Humans; Kinase inhibitors; Mammalian target of rapamycin; Medical sciences; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; mTOR; Pharmacology. Drug treatments; Phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - chemistry; Protein Kinases - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.08.069

The discovery and optimisation of a novel series of inhibitors of mTOR kinase are described. Compound 15 has low nanomolar potency against mTOR kinase and is highly selective relative to PI3Kα. A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.