Depletion of creatine phosphagen energetics with a covalent creatine kinase inhibitor

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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)815-824
Number of pages10
JournalNature Chemical Biology
Volume19
Issue number7
DOIs
StatePublished - Jul 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

This work was supported by the Claudia Adams Barr Program (E.T.C.), the Lavine Family Fund (E.T.C.), the Pew Charitable Trust (E.T.C.), National Institutes of Health (NIH) CA259739-01 (E.T.C.), AG071966-01 (E.T.C.), NIH DK123095 (E.T.C.), The Smith Family Foundation (E.T.C.), T32CA236754 (N.D.), the National Cancer Center (NCI) (H.X. and N.D.) NCI R35 CA210030 (K. Stegmaier) and P50 CA206963 (K. Stegmaier), K99AG073461 (H.X.), NCI R35 CA231991 (B.F.C.), the Linde Family Foundation (S.D.-P.), the Doris Duke Charitable Foundation (S.D.-P.), Deerfield 3DC (S.D.-P.), Taiho Pharmaceuticals (S.D.-P.), NCI K99 CA263161 (S.L), and NIH (4R00DK123321-03), Mathers Foundation (MF-2204-02617) and American Cancer Society (DBG-23-983219-01-TBE) (E.L.M). S.L. is a Fellow of the Leukemia & Lymphoma Society. This work was based upon research conducted at the Northeastern Collaborative Access Team beamlines, which were funded by the National Institute of General Medical Sciences from the National Institutes of Health (P30 GM124165). The Eiger 16M detector on the 24-ID-E beamline was funded by a NIH-Office of Research Infrastructure Programs High-End Instrumentation grant (S10OD021527). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. This work was supported by the Claudia Adams Barr Program (E.T.C.), the Lavine Family Fund (E.T.C.), the Pew Charitable Trust (E.T.C.), National Institutes of Health (NIH) CA259739-01 (E.T.C.), AG071966-01 (E.T.C.), NIH DK123095 (E.T.C.), The Smith Family Foundation (E.T.C.), T32CA236754 (N.D.), the National Cancer Center (NCI) (H.X. and N.D.) NCI R35 CA210030 (K. Stegmaier) and P50 CA206963 (K. Stegmaier), K99AG073461 (H.X.), NCI R35 CA231991 (B.F.C.), the Linde Family Foundation (S.D.-P.), the Doris Duke Charitable Foundation (S.D.-P.), Deerfield 3DC (S.D.-P.), Taiho Pharmaceuticals (S.D.-P.), NCI K99 CA263161 (S.L), and NIH (4R00DK123321-03), Mathers Foundation (MF-2204-02617) and American Cancer Society (DBG-23-983219-01-TBE) (E.L.M). S.L. is a Fellow of the Leukemia & Lymphoma Society. This work was based upon research conducted at the Northeastern Collaborative Access Team beamlines, which were funded by the National Institute of General Medical Sciences from the National Institutes of Health (P30 GM124165). The Eiger 16M detector on the 24-ID-E beamline was funded by a NIH-Office of Research Infrastructure Programs High-End Instrumentation grant (S10OD021527). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

FundersFunder number
Lavine Family Fund
Linde Family Foundation
National Institutes of HealthAG071966-01, DK123095, CA259739-01
U.S. Department of Energy
American Cancer SocietyDBG-23-983219-01-TBE
National Cancer InstituteK99AG073461, P50 CA206963, R35 CA210030
National Institute of General Medical SciencesP30 GM124165
Doris Duke Charitable Foundation
Pew Charitable Trusts
G. Harold and Leila Y. Mathers Charitable FoundationMF-2204-02617
Richard and Susan Smith Family FoundationT32CA236754
Leukemia and Lymphoma Society
Office of Science
Argonne National LaboratoryDE-AC02-06CH11357
National Cancer Center
Taiho PharmaceuticalK99 CA263161, 4R00DK123321-03
Office of Research Infrastructure Programs, National Institutes of HealthS10OD021527

    Fingerprint

    Dive into the research topics of 'Depletion of creatine phosphagen energetics with a covalent creatine kinase inhibitor'. Together they form a unique fingerprint.

    Cite this