title: Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.
abstract: 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.
authors: Oncology Innovative Medicines, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors: Kurt G
authors: KG
authors: Pike
authors: Jeff
authors: J
authors: Morris
authors: Linette
authors: L
authors: Ruston
authors: Sarah L
authors: SL
authors: Pass
authors: Ryan
authors: R
authors: Greenwood
authors: Emma J
authors: EJ
authors: Williams
authors: Julie
authors: J
authors: Demeritt
authors: Janet D
authors: JD
authors: Culshaw
authors: Kristy
authors: K
authors: Gill
authors: Martin
authors: M
authors: Pass
authors: M Raymond V
authors: MR
authors: Finlay
authors: Catherine J
authors: CJ
authors: Good
authors: Craig A
authors: CA
authors: Roberts
authors: Gordon S
authors: GS
authors: Currie
authors: Kevin
authors: K
authors: Blades
authors: Jonathan M
authors: JM
authors: Eden
authors: Stuart E
authors: SE
authors: Pearson
mesh_terms: D002478:Cells, Cultured; D055808:Drug Discovery; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008958:Models, Molecular; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000598573:1-(4-(4-(1-cyclopropylsulfonylcyclopropyl)-6-(3-methylmorpholin-4-yl)pyrimidin-2-yl)phenyl)-3-(2-hydroxyethyl)thiourea; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D013890:Thiourea