1821428-35-6 Usage
Biological Activity
azd0156 is an atm kinase inhibitor.ataxia telangiectasia mutant (atm), a serine/threonine protein kinase from the phosphatidylinositol 3-kinase-related kinase (pikk) family of protein kinases, plays a critical role in the cellular dna damage response signalling activated by dna double strand breaks. activated atm can promote dna repair and s/g1-cell cycle checkpoints to prevent premature mitosis, maintain genomic integrity as well as promote appropriate cell survival or death pathways. thus, atm inhibitor can represent a promosing clinical opportunity to hyper-sensitize tumors to chemo/radiotherapy.
in vitro
azd0156 was identified as a first in class orally available atm inhibitor, showing sub-nanomolar potency in cell based assays of atm inhibition. moreover, azd0156 had selectivities of greater than 1000 fold over other members of the pikk family enzymes [1].
in vivo
in animal study, azd0156 displayed excellent preclinical pk properties including oral bioavailability. additionally, in mouse xenograft models, azd0156 showed robust efficacy after oral administration when combined with double strand breaks (dsb) inducing agents [1].
references
[1] kurt g. pike. identifying high quality, potent and selective inhibitors of atm kinase: discovery of azd0156. [abstract]. in: proceedings of the 107th annual meeting of the american association for cancer research; 2016 apr 16-20; new orleans, la. philadelphia (pa): aacr; cancer res 2016;76(14 suppl):abstract nr 4859.[2] https://clinicaltrials. gov/ct2/show/nct02588105 term=azd0156&rank=1
Check Digit Verification of cas no
The CAS Registry Mumber 1821428-35-6 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,8,2,1,4,2 and 8 respectively; the second part has 2 digits, 3 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 1821428-35:
(9*1)+(8*8)+(7*2)+(6*1)+(5*4)+(4*2)+(3*8)+(2*3)+(1*5)=156
156 % 10 = 6
So 1821428-35-6 is a valid CAS Registry Number.
1821428-35-6Relevant 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 (2018/05/14)
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.
