7zi5 | pdb_00007zi5

Crystal structure of dCK C4S-S74E mutant in complex with UDP and the OR0274 inhibitor

spinqualitylabelsall models 7zi5, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zi5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: J9I, NA, UDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DCK_HUMAN Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents. Publication Abstract from PubMed Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations. This strategy allows an acceleration of the hit-to-lead process by gradually implementing key chemical modifications to increase affinity and activity. Our lead compound, OR0642, is more than 1000 times more potent than its initial parent compound, masitinib, previously identified from a drug repositioning approach. OR0642 in combination with a physiological inhibitor of the de novo pathway doubled the survival rate in a human T-cell acute lymphoblastic leukemia patient-derived xenograft mouse model, demonstrating the proof-of-concept of this drug design strategy. From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia.,Saez-Ayala M, Hoffer L, Abel S, Ben Yaala K, Sicard B, Andrieu GP, Latiri M, Davison EK, Ciufolini MA, Bremond P, Rebuffet E, Roche P, Derviaux C, Voisset E, Montersino C, Castellano R, Collette Y, Asnafi V, Betzi S, Dubreuil P, Combes S, Morelli X Nat Commun. 2023 May 29;14(1):3079. doi: 10.1038/s41467-023-38668-2. PMID:37248212 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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