7zi7
Crystal structure of dCK C4S-S74E mutant in complex with UDP and the OR0345 inhibitorCrystal structure of dCK C4S-S74E mutant in complex with UDP and the OR0345 inhibitor
Structural highlights
FunctionDCK_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.[1] [2] Publication Abstract from PubMedCancer 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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