4Q19

Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 5 {5-(4-{[(4,6-DIAMINOPYRIMIDIN-2-YL)SULFANYL]METHYL}-5-PROPYL-1,3-THIAZOL-2-YL)-2-METHOXYPHENOL}

Summary for 4Q19

• Entry DOI: 10.2210/pdb4q19/pdb
• Related: 4Q18 4Q1A 4Q1B 4Q1C 4Q1D 4Q1E 4Q1F
• Descriptor: Deoxycytidine kinase, 5-(4-(((4,6-diaminopyrimidin-2-yl)thio)methyl)-5-propylthiazol-2-yl)-2-methoxyphenol, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: phosphoryl transfer, phosphorylation, deoxycytidine, transferase, inhibitor complex, kinase, 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: 67018.62

Authors

Nomme, J.,Lavie, A. (deposition date: 2014-04-03, release date: 2014-11-05, Last modification date: 2023-09-20)

Primary citation

Nomme, J.,Li, Z.,Gipson, R.M.,Wang, J.,Armijo, A.L.,Le, T.,Poddar, S.,Smith, T.,Santarsiero, B.D.,Nguyen, H.A.,Czernin, J.,Alexandrova, A.N.,Jung, M.E.,Radu, C.G.,Lavie, A.
Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.
J.Med.Chem., 57:9480-9494, 2014

PubMed Abstract: Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.

PubMed: 25341194
DOI: 10.1021/jm501124j

Experimental method

X-RAY DIFFRACTION (2.09 Å)