Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2
| Autor: | Gordon S. Currie, Kurt Gordon Pike, Janet D. Culshaw, Martin Pass, Kristy Gill, M. Raymond V. Finlay, Stuart E. Pearson, Jonathan M. Eden, Craig A. Roberts, Linette Ruston, Kevin Blades, Sarah L. Pass, Catherine Good, Ryan Greenwood, Morris Jeffrey James, Julie Demeritt, Emma J. Williams |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Molecular Structure Chemistry Drug discovery TOR Serine-Threonine Kinases High-throughput screening Thiourea Mechanistic Target of Rapamycin Complex 2 mTORC1 Mechanistic Target of Rapamycin Complex 1 Combinatorial chemistry mTORC2 Chemical space Structure-Activity Relationship Pyrimidines Multiprotein Complexes Drug Discovery Hepatocytes Humans Molecular Medicine Potency Structure–activity relationship Solubility Protein Kinase Inhibitors Cells Cultured |
| Zdroj: | Journal of Medicinal Chemistry. 58:2326-2349 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm501778s |
| Popis: | High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate. |
| Databáze: | OpenAIRE |
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