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

Magali Saez-Ayala (), Laurent Hoffer, Sébastien Abel, Khaoula Ben Yaala, Benoit Sicard, Guillaume P. Andrieu, Mehdi Latiri, Emma K. Davison, Marco A. Ciufolini, Paul Brémond, Etienne Rebuffet, Philippe Roche, Carine Derviaux, Edwige Voisset, Camille Montersino, Remy Castellano, Yves Collette, Vahid Asnafi, Stéphane Betzi, Patrice Dubreuil (), Sébastien Combes () and Xavier Morelli ()
Additional contact information
Magali Saez-Ayala: Aix-Marseille Univ, Institut Paoli-Calmettes
Laurent Hoffer: Aix-Marseille Univ, Institut Paoli-Calmettes
Sébastien Abel: Aix-Marseille Univ, Institut Paoli-Calmettes
Khaoula Ben Yaala: Aix-Marseille Univ, Institut Paoli-Calmettes
Benoit Sicard: Aix-Marseille Univ, Institut Paoli-Calmettes
Guillaume P. Andrieu: Université de Paris
Mehdi Latiri: Université de Paris
Emma K. Davison: University of British Columbia
Marco A. Ciufolini: Aix-Marseille Univ, Institut Paoli-Calmettes
Paul Brémond: Aix-Marseille Univ, Institut Paoli-Calmettes
Etienne Rebuffet: Aix-Marseille Univ, Institut Paoli-Calmettes
Philippe Roche: Aix-Marseille Univ, Institut Paoli-Calmettes
Carine Derviaux: Aix-Marseille Univ, Institut Paoli-Calmettes
Edwige Voisset: Aix-Marseille Univ, Institut Paoli-Calmettes
Camille Montersino: Aix-Marseille Univ, Institut Paoli-Calmettes
Remy Castellano: Aix-Marseille Univ, Institut Paoli-Calmettes
Yves Collette: Aix-Marseille Univ, Institut Paoli-Calmettes
Vahid Asnafi: Université de Paris
Stéphane Betzi: Aix-Marseille Univ, Institut Paoli-Calmettes
Patrice Dubreuil: Aix-Marseille Univ, Institut Paoli-Calmettes
Sébastien Combes: Aix-Marseille Univ, Institut Paoli-Calmettes
Xavier Morelli: Aix-Marseille Univ, Institut Paoli-Calmettes

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38668-2

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