title: Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.
abstract: The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. kurt.pike@astrazeneca.com
authors: Kurt G
authors: KG
authors: Pike
authors: Karine
authors: K
authors: Malagu
authors: Marc G
authors: MG
authors: Hummersone
authors: Keith A
authors: KA
authors: Menear
authors: Heather M E
authors: HM
authors: Duggan
authors: Sylvie
authors: S
authors: Gomez
authors: Niall M B
authors: NM
authors: Martin
authors: Linette
authors: L
authors: Ruston
authors: Sarah L
authors: SL
authors: Pass
authors: Martin
authors: M
authors: Pass
mesh_terms: D001549:Benzamides; D048708:Cell Growth Processes / Q000187:drug effects; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D009025:Morpholines; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C585537:vistusertib; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases