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dc.creatorBon, Corentin
dc.creatorSi, Yang
dc.creatorPernak, Melanie
dc.creatorBarbachowska, Magdalena
dc.creatorLevi-Acobas, Eva
dc.creatorCadet Daniel, Veronique
dc.creatorJallet, Corinne
dc.creatorRužić, Dušan
dc.creatorĐoković, Nemanja
dc.creatorĐikić, Teodora
dc.creatorNikolić, Katarina
dc.creatorHalby, Ludovic
dc.creatorArimondo, Paola B.
dc.date.accessioned2021-09-15T09:07:13Z
dc.date.available2021-09-15T09:07:13Z
dc.date.issued2021
dc.identifier.issn1420-3049
dc.identifier.urihttps://farfar.pharmacy.bg.ac.rs/handle/123456789/3954
dc.description.abstractHistone methyltransferase DOT1L catalyzes mono-, di-and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.
dc.publisherMDPI
dc.relationLe Comitéde Paris de la Ligue contre la Cancer (project Epi-Med 2020-2021) to PBA.
dc.relationHubert Curien Partnership Project for collaboration France-Serbia 2020- 2022 (Program Pavle Savic 2020) to PBA and KN
dc.relationEU COST CM1406 Epigenetic Chemical Biology program.
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceMolecules
dc.subjectBisubstrates
dc.subjectDOT1L
dc.subjectHistone methylation
dc.subjectHMT inhibitors
dc.subjectMLL rearranged leukemia
dc.subjectRational drug design
dc.titleSynthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein
dc.typearticle
dc.rights.licenseBY
dcterms.abstractРужић, Душан; Ђоковић, Немања; Ђикић, Теодора; Николић, Катарина; Бон, Цорентин; Си, Yанг; Пернак, Мелание; Барбацхоwска, Магдалена; Леви-Aцобас, Ева; Цадет Даниел, Верониqуе; Јаллет, Цоринне; Халбy, Лудовиц; Aримондо, Паола Б.;
dc.citation.volume26
dc.citation.issue17
dc.identifier.doi10.3390/molecules26175300
dc.identifier.scopus2-s2.0-85114232085
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs/bitstream/id/9141/Synthesis_and_Biological_pub_2021.pdf
dc.type.versionpublishedVersion


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