KU 55933 is a potent and specific ATM kinase inhibitor that sensitizes human tumor cells to ionizing radiation and chemotherapeutic agents[1]. KU 55933 has an IC50 of 13nM and Ki of 2.2nM in vitro[2].
In vitro, The ATM inhibitor KU 55933 (10μM; 1h) suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt[3]. Inhibition of ATM with KU 55933 (10μM; 24h or 72h) sensitizes endometrial cancer cell lines to Olaparib[4]. KU 55933 (0.01-20μM; 24h) is neuroprotective against the doxorubicin-induced cell damage in UN- and RA-SH-SY5Y cells[5].
In vivo, Administration of KU 55933 (8mg/kg; 12 weeks; i.v.) to apolipoprotein E-deficient mice inhibited Smad1/5 activation in endothelial cells (ECs) in atherosclerosis-susceptible regions, thereby suppressing endothelial cell proliferation and inflammation and attenuating atherosclerotic lesions in these mice[3]. KU 55933 (1mg/kg; 4 weeks; i.p.) treatment inhibits tumor growth and metastasis in mouse mammary tumors in vivo through the inhibition of GLUT1 translocation and vimentin expression[6].
References:
[1] Wei SY, Fu WS, Liu CH, et al. Identification of KU-55933 as an anti-atherosclerosis compound by using a hemodynamic-based high-throughput drug screening platform. Proc Natl Acad Sci U S A. 2024 Jan 30;121(5):e2318718121.
[2] Golding SE, Rosenberg E, Valerie N, et al. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther. 2009 Oct;8(10):2894-902.
[3] Zhang A, Zhang L, Xie X, et al. Inhibition of ATM with KU-55933 Sensitizes Endometrial Cancer Cell Lines to Olaparib. Onco Targets Ther. 2023 Dec 19;16:1061-1071.
[4] Chwastek J, Jantas D, Lasoń W. The ATM kinase inhibitor KU-55933 provides neuroprotection against hydrogen peroxide-induced cell damage via a γH2AX/p-p53/caspase-3-independent mechanism: Inhibition of calpain and cathepsin D. Int J Biochem Cell Biol. 2017 Jun;87:38-53.
[5] Li Y, Yang DQ. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 2010 Jan;9(1):113-25.
[6] Harris BRE, Zhang Y, Tao J, et al. ATM inhibitor KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake in aggressive cancer cells with sustained activation of Akt. FASEB J. 2021 Apr;35(4):e21264.
KU 55933是一种高效且特异的ATM激酶抑制剂，能够使人类肿瘤细胞对电离辐射和化疗药物更加敏感[1]。KU 55933在体外的IC₅₀值为13nM，Ki值为2.2nM[2]。
在体外实验中，ATM抑制剂KU 55933（10μM; 1小时）通过阻断过度激活的Akt，抑制癌细胞的增殖并诱导凋亡[3]。通过KU 55933（10μM; 24小时或72小时）抑制ATM，可使子宫内膜癌细胞系对奥拉帕尼更加敏感[4]。KU 55933（0.01-20μM; 24小时）对阿霉素诱导的UN-和RA-SH-SY5Y细胞损伤具有神经保护作用[5]。
在体内实验中，对缺乏载脂蛋白E的小鼠给予KU 55933（8mg/kg; 12周; 静脉注射），抑制了易患动脉粥样硬化区域的内皮细胞（ECs）中Smad1/5的激活，从而抑制了内皮细胞的增殖和炎症，并减轻了这些小鼠的动脉粥样硬化病变[3]。KU 55933治疗通过抑制GLUT1的转位和波形蛋白的表达，在体内抑制小鼠乳腺肿瘤的生长和转移[6]。