title: Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity.
abstract: ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.
authors: AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. kevin.foote@astrazeneca.com
authors: Kevin M
authors: KM
authors: Foote
authors: Kevin
authors: K
authors: Blades
authors: Anna
authors: A
authors: Cronin
authors: Shaun
authors: S
authors: Fillery
authors: Sylvie S
authors: SS
authors: Guichard
authors: Lorraine
authors: L
authors: Hassall
authors: Ian
authors: I
authors: Hickson
authors: Xavier
authors: X
authors: Jacq
authors: Philip J
authors: PJ
authors: Jewsbury
authors: Thomas M
authors: TM
authors: McGuire
authors: J Willem M
authors: JW
authors: Nissink
authors: Rajesh
authors: R
authors: Odedra
authors: Ken
authors: K
authors: Page
authors: Paula
authors: P
authors: Perkins
authors: Abid
authors: A
authors: Suleman
authors: Kin
authors: K
authors: Tam
authors: Pia
authors: P
authors: Thommes
authors: Rebecca
authors: R
authors: Broadhurst
authors: Christine
authors: C
authors: Wood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C581009:4-(4-(3-methylmorpholin-4-yl)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-2-yl)-1H-indole; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases