使用共价肌酸激酶抑制剂耗竭肌酸磷酸能量学。
Depletion of creatine phosphagen energetics with a covalent creatine kinase inhibitor.
发表日期：2023 Feb 23
作者：
Narek Darabedian, Wenzhi Ji, Mengyang Fan, Shan Lin, Hyuk-Soo Seo, Ekaterina V Vinogradova, Tomer M Yaron, Evanna L Mills, Haopeng Xiao, Kristine Senkane, Emily M Huntsman, Jared L Johnson, Jianwei Che, Lewis C Cantley, Benjamin F Cravatt, Sirano Dhe-Paganon, Kimberly Stegmaier, Tinghu Zhang, Nathanael S Gray, Edward T Chouchani
来源：
Nature Chemical Biology
摘要：
肌酸激酶（CK）在能量需求增加的时期，例如在快速的合成代谢和生长期，提供局部的ATP产生。因此，肌酸能量已经成为许多快速增殖癌症的主要代谢负担。目前尚不清楚CK是否能作为治疗靶点，因为尚未开发出有效且具有选择性的CK抑制剂。在这里，我们利用所有CK亚型中都存在的一个活性位点半胱氨酸来开发选择性共价抑制剂CKi以抑制肌酸磷酸灰化作用。通过深度化学蛋白质组学，我们发现CKi在细胞中选择性地与CKs的活性位点半胱氨酸结合。CKi与肌酸激酶B的共结晶结构表明了活性位点的抑制，从而防止双向磷酸转移。在细胞中，CKi及其类似物选择性地迅速降低肌酸磷酸，仅对CK依赖性的急性髓性白血病产生毒性作用。最后，我们使用CKi揭示了CKs在调节巨噬细胞的前炎性细胞因子产生中的重要作用。 ©2023.此作者，根据Springer Nature America，Inc.的独家许可。
Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has emerged as a major metabolic liability in many rapidly proliferating cancers. Whether CKs can be targeted therapeutically is unknown because no potent or selective CK inhibitors have been developed. Here we leverage an active site cysteine present in all CK isoforms to develop a selective covalent inhibitor of creatine phosphagen energetics, CKi. Using deep chemoproteomics, we discover that CKi selectively engages the active site cysteine of CKs in cells. A co-crystal structure of CKi with creatine kinase B indicates active site inhibition that prevents bidirectional phosphotransfer. In cells, CKi and its analogs rapidly and selectively deplete creatine phosphate, and drive toxicity selectively in CK-dependent acute myeloid leukemia. Finally, we use CKi to uncover an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.