4q1e

Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 10 {2-{[(1R/S)-1-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]-5-methyl-1,3-thiazol 4-yl}ethyl]sulfanyl}pyrimidine-4,6-diamine}

spinqualitylabelsall models 4q1e, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4q1e is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2Y7, 2Y8, UDP Related: 4q18, 4q19, 4q1a, 4q1b, 4q1c, 4q1d, 4q1f Activity: Deoxycytidine kinase, with EC number 2.7.1.74 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.,Nomme J, Li Z, Gipson RM, Wang J, Armijo AL, Le T, Poddar S, Smith T, Santarsiero BD, Nguyen HA, Czernin J, Alexandrova AN, Jung ME, Radu CG, Lavie A J Med Chem. 2014 Oct 23. PMID:25341194 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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