Structure-based optimization of morpholino-triazines as PI3K and mTOR inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 2; pp. 1009 - 1013
• Main Authors: Poulsen, Anders, Williams, Meredith, Nagaraj, Harish Mysore, William, Anthony D., Wang, Haishan, Soh, Chang Kai, Xiong, Zheng Chang, Dymock, Brian
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.01.2012; Elsevier
• Subjects: Biological and medical sciences; Cell Line, Tumor; Docking; Dose-Response Relationship, Drug; enzyme inhibitors; Humans; Mammalian target of rapamycin; Medical sciences; Models, Molecular; Molecular Structure; molecular weight; Morpholines - chemistry; Morpholines - pharmacology; Pharmacology. Drug treatments; Phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Selectivity; Stereoisomerism; Structure-Activity Relationship; Structure-based design; TOR Serine-Threonine Kinases - antagonists & inhibitors; triazines; Triazines - chemistry; Triazines - pharmacology; Docking; Selectivity; Phosphatidylinositol 3-kinase; Structure-based design; Mammalian target of rapamycin; Antineoplastic agent; Sirolimus; Phospholipid; Molecular interaction; Morpholine derivatives; Modeling; Optimization; Macrocycle; Phosphatidylinositol; Structure activity relation; Molecular model; mTOR inhibitor; Protein synthesis inhibitor; Lactone; Complex lipid; Macrolide; Immunomodulator; Antibiotic; Triazine derivatives; Immunosuppressive agent
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.001

A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kα. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kα was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties.