作者
Stephen T Durant, Li Zheng, Yingchun Wang, Kan Chen, Lingli Zhang, Tianwei Zhang, Zhenfan Yang, Lucy Riches, Antonio G Trinidad, Jacqueline HL Fok, Tom Hunt, Kurt G Pike, Joanne Wilson, Aaron Smith, Nicola Colclough, Venkatesh Pilla Reddy, Andrew Sykes, Annika Janefeldt, Peter Johnström, Katarina Varnäs, Akihiro Takano, Stephanie Ling, Jonathan Orme, Jonathan Stott, Caroline Roberts, Ian Barrett, Gemma Jones, Martine Roudier, Andrew Pierce, Jasmine Allen, Jenna Kahn, Amrita Sule, Jeremy Karlin, Anna Cronin, Melissa Chapman, Kristoffer Valerie, Ruth Illingworth, Martin Pass
发表日期
2018/6/20
期刊
Science advances
卷号
4
期号
6
页码范围
eaat1719
出版商
American Association for the Advancement of Science
简介
Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase–related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography …
学术搜索中的文章
ST Durant, L Zheng, Y Wang, K Chen, L Zhang… - Science advances, 2018