5G55

3-Quinoline Carboxamides inhibitors of Pi3K

Summary for 5G55

• Entry DOI: 10.2210/pdb5g55/pdb
• Descriptor: PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, 6-cyano-4-[[(1R)-1-(4-methylphenyl)ethyl]amino]quinoline-3-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transferase, atm
• Biological source: HOMO SAPIENS
• Total number of polymer chains: 1
• Total formula weight: 111182.61

Authors

Edman, K.,Phillips, C. (deposition date: 2016-05-20, release date: 2016-08-03, Last modification date: 2024-05-08)

Primary citation

Degorce, S.L.,Barlaam, B.,Cadogan, E.,Dishington, A.P.,Ducray, R.,Glossop, S.C.,Hassall, L.A.,Lach, F.,Lau, A.,Mcguire, T.M.,Nowak, T.,Ouvry, G.,Pike, K.G.,Thomason, A.G.
Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (Atm) Kinase.
J.Med.Chem., 59:6281-, 2016

PubMed Abstract: 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.

PubMed: 27259031
DOI: 10.1021/ACS.JMEDCHEM.6B00519

Experimental method

X-RAY DIFFRACTION (2.45 Å)