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Article Dans Une Revue Nature Communications Année : 2023

From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia

Guillaume Andrieu
Emma Davison

Résumé

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.
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Dates et versions

hal-04237671 , version 1 (11-10-2023)

Identifiants

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Magali Saez-Ayala, Laurent Hoffer, Sébastien Abel, Khaoula Ben Yaala, Benoit Sicard, et al.. From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia. Nature Communications, 2023, 14 (1), pp.3079. ⟨10.1038/s41467-023-38668-2⟩. ⟨hal-04237671⟩
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