4KCG

Human dCK C4S-S74E mutant in complex with UDP and the DI-39 inhibitor

Summary for 4KCG

• Entry DOI: 10.2210/pdb4kcg/pdb
• Descriptor: Deoxycytidine kinase, N-{2-[5-(4-{[(4,6-diaminopyrimidin-2-yl)sulfanyl]methyl}-5-propyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]ethyl}methanesulfonamide, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: phosphoryl transfer, phosphorylation, deoxycytidine, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P27707
• Total number of polymer chains: 2
• Total formula weight: 67260.94

Authors

Nomme, J.,Lavie, A. (deposition date: 2013-04-24, release date: 2014-03-12, Last modification date: 2023-09-20)

Primary citation

Nathanson, D.A.,Armijo, A.L.,Tom, M.,Li, Z.,Dimitrova, E.,Austin, W.R.,Nomme, J.,Campbell, D.O.,Ta, L.,Le, T.M.,Lee, J.T.,Darvish, R.,Gordin, A.,Wei, L.,Liao, H.I.,Wilks, M.,Martin, C.,Sadeghi, S.,Murphy, J.M.,Boulos, N.,Phelps, M.E.,Faull, K.F.,Herschman, H.R.,Jung, M.E.,Czernin, J.,Lavie, A.,Radu, C.G.
Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication.
J.Exp.Med., 211:473-486, 2014

PubMed Abstract: Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.

PubMed: 24567448
DOI: 10.1084/jem.20131738

Experimental method

X-RAY DIFFRACTION (2.09 Å)