Title | Depletion of creatine phosphagen energetics with a covalent creatine kinase inhibitor. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Darabedian N, Ji W, Fan M, Lin S, Seo H-S, Vinogradova EV, Yaron TM, Mills EL, Xiao H, Senkane K, Huntsman EM, Johnson JL, Che J, Cantley LC, Cravatt BF, Dhe-Paganon S, Stegmaier K, Zhang T, Gray NS, Chouchani ET |
Journal | Nat Chem Biol |
Volume | 19 |
Issue | 7 |
Pagination | 815-824 |
Date Published | 2023 Jul |
ISSN | 1552-4469 |
Keywords | Creatine, Creatine Kinase, Cysteine, Phosphotransferases, Protein Isoforms |
Abstract | 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. |
DOI | 10.1038/s41589-023-01273-x |
Alternate Journal | Nat Chem Biol |
PubMed ID | 36823351 |
PubMed Central ID | 5540325 |
Grant List | K99 AG073461 / AG / NIA NIH HHS / United States K99 CA263161 / CA / NCI NIH HHS / United States S10 OD021527 / OD / NIH HHS / United States P30 GM124165 / GM / NIGMS NIH HHS / United States R00 DK123321 / DK / NIDDK NIH HHS / United States R35 CA231991 / CA / NCI NIH HHS / United States P50 CA206963 / CA / NCI NIH HHS / United States R35 CA210030 / CA / NCI NIH HHS / United States T32 CA236754 / CA / NCI NIH HHS / United States R01 DK123095 / DK / NIDDK NIH HHS / United States R01 AG071966 / AG / NIA NIH HHS / United States R21 CA259739 / CA / NCI NIH HHS / United States |