Background
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].
Clinical trial: AZD0156 is now undergoing early clinical assessment to investigate the safety and preliminary efficacy at increasing doses alone or in combination with other anti-cancer treatment in patients with advanced cancer [2].
参考文献:
[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
Protocol
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Cell experiment:
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HT29 cells are seeded into 384 well assay plates at a density of 6000 cells/well in 40 μL EMEM medium containing 1% L glutamine and 10% FBS and allowed to adhere overnight. The following morning compound of Formula (I) in 100% DMSO is added to assay plates by acoustic dispensing. After lh incubation at 37°C and 5% C02,?40 nL of 3 mM 4NQO in 100% DMSO is added to all wells by acoustic dispensing, except minimum control wells which are left untreated with 4NQO to generate a null response control. Plates are returned to the incubator for a further lh. Then cells are fixed by adding 20 μL of 3.7% formaldehyde in PBS solution and incubating for 20 mins at r.t.. Then 20 μL of 0.1% Triton XI 00 in PBS is added and incubated for 10 minutes at r.t., to permeabalise cells. Then the plates are washed once with 50 μL/well PBS, using a Biotek EL405 plate washer.
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参考文献:
[1]. Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer.
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