7ZIA

Crystal structure of dCK C4S-S74E mutant in complex with UDP and the OR0634 inhibitor

Summary for 7ZIA

• Entry DOI: 10.2210/pdb7zia/pdb
• Descriptor: Deoxycytidine kinase, URIDINE-5'-DIPHOSPHATE, 2-[2-[[2-methyl-5-[6-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]phenyl]-propyl-amino]-1,3-thiazol-4-yl]pyrimidine-4,6-diamine, ... (5 entities in total)
• Functional Keywords: inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33708.52

Authors

Ben-Yaala, K.,Saez-Ayala, M.,Betzi, S.,Rebuffet, E.,Morelli, X. (deposition date: 2022-04-07, release date: 2023-06-07, Last modification date: 2024-02-07)

Primary citation

Saez-Ayala, M.,Hoffer, L.,Abel, S.,Ben Yaala, K.,Sicard, B.,Andrieu, G.P.,Latiri, M.,Davison, E.K.,Ciufolini, M.A.,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.
From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia.
Nat Commun, 14:3079-3079, 2023

PubMed Abstract: 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.

PubMed: 37248212
DOI: 10.1038/s41467-023-38668-2

Experimental method

X-RAY DIFFRACTION (1.7 Å)