From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38668-2 |
| _version_ | 1797811400422195200 |
|---|---|
| author | 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 Xavier Morelli |
| author_facet | 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 Xavier Morelli |
| author_sort | Magali Saez-Ayala |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T07:22:04Z |
| format | Article |
| id | doaj.art-455ce64ed58b44c582373ae5edcfa6e5 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T07:22:04Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-455ce64ed58b44c582373ae5edcfa6e52023-06-04T11:33:45ZengNature PortfolioNature Communications2041-17232023-05-0114111710.1038/s41467-023-38668-2From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemiaMagali Saez-Ayala0Laurent Hoffer1Sébastien Abel2Khaoula Ben Yaala3Benoit Sicard4Guillaume P. Andrieu5Mehdi Latiri6Emma K. Davison7Marco A. Ciufolini8Paul Brémond9Etienne Rebuffet10Philippe Roche11Carine Derviaux12Edwige Voisset13Camille Montersino14Remy Castellano15Yves Collette16Vahid Asnafi17Stéphane Betzi18Patrice Dubreuil19Sébastien Combes20Xavier Morelli21Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesInstitut Necker Enfants Malades (INEM), INSERM, Hôpital Necker Enfants-Malades, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Université de ParisInstitut Necker Enfants Malades (INEM), INSERM, Hôpital Necker Enfants-Malades, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Université de ParisDepartment of Chemistry, Faculty of Science, University of British ColumbiaCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesInstitut Necker Enfants Malades (INEM), INSERM, Hôpital Necker Enfants-Malades, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Université de ParisCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesCentre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-CalmettesAbstract 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.https://doi.org/10.1038/s41467-023-38668-2 |
| spellingShingle | 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 Xavier Morelli From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia Nature Communications |
| title | From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia |
| title_full | From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia |
| title_fullStr | From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia |
| title_full_unstemmed | From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia |
| title_short | From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia |
| title_sort | from a drug repositioning to a structure based drug design approach to tackle acute lymphoblastic leukemia |
| url | https://doi.org/10.1038/s41467-023-38668-2 |
| work_keys_str_mv | AT magalisaezayala fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT laurenthoffer fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT sebastienabel fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT khaoulabenyaala fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT benoitsicard fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT guillaumepandrieu fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT mehdilatiri fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT emmakdavison fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT marcoaciufolini fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT paulbremond fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT etiennerebuffet fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT philipperoche fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT carinederviaux fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT edwigevoisset fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT camillemontersino fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT remycastellano fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT yvescollette fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT vahidasnafi fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT stephanebetzi fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT patricedubreuil fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT sebastiencombes fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia AT xaviermorelli fromadrugrepositioningtoastructurebaseddrugdesignapproachtotackleacutelymphoblasticleukemia |