122794-99-4Relevant articles and documents
The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one)
Pike, Kurt G.,Barlaam, Bernard,Cadogan, Elaine,Campbell, Andrew,Chen, Yingxue,Colclough, Nicola,Davies, Nichola L.,De-Almeida, Camila,Degorce, Sebastien L.,Didelot, Myriam,Dishington, Allan,Ducray, Richard,Durant, Stephen T.,Hassall, Lorraine A.,Holmes, Jane,Hughes, Gareth D.,Macfaul, Philip A.,Mulholland, Keith R.,McGuire, Thomas M.,Ouvry, Gilles,Pass, Martin,Robb, Graeme,Stratton, Natalie,Wang, Zhenhua,Wilson, Joanne,Zhai, Baochang,Zhao, Kang,Al-Huniti, Nidal
, p. 3823 - 3841 (2018)
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5-c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
BENZO[H][1,6] NAPHTHYRIDIN-2(1H)-ONES AS BMX INHIBITORS, FOR USE AGAINST CANCER
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Page/Page column 45; 48, (2020/12/29)
The present invention provides a compound of formula (I) and its use in methods of treatment, including the treatment of cancer. The compound has the structure shown below where D is an acceptor group and -A-, -L-, R7 are as discussed in the ap
Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold
Al-Sanea, Mohammad M.
, (2020/04/24)
Background. CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators. Methods. A series of nine 4-phenylaminoquinoline scaffold-based compounds 5a-i was synthesized, and biologically evaluated as potential CDK8/CycC complex inhibitors. Results. The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4-phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive. Discussion. The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound 5d showed submicromolar potency against CDK8/CycC (IC50 = 0.639 μM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.