Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase.
A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.|Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France.
Sébastien L
SL
Degorce
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Bernard
B
Barlaam
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Elaine
E
Cadogan
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Allan
A
Dishington
Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France.
Richard
R
Ducray
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Steven C
SC
Glossop
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Lorraine A
LA
Hassall
Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France.
Franck
F
Lach
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Alan
A
Lau
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Thomas M
TM
McGuire
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Thorsten
T
Nowak
Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France.
Gilles
G
Ouvry
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Kurt G
KG
Pike
Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Andrew G
AG
Thomason
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C541322:quinoline-3-carboxamide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins