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Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

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dc.contributor.authorShao, H.
dc.contributor.authorFoley, D.W.
dc.contributor.authorHuang, S.
dc.contributor.authorAbbas, A.Y.
dc.contributor.authorLam, F.
dc.contributor.authorGershkovich, P.
dc.contributor.authorBradshaw, T.D.
dc.contributor.authorPepper, C.
dc.contributor.authorFischer, P.M.
dc.contributor.authorWang, S.
dc.date.issued2021
dc.descriptionData source: Supplementary data, https://doi.org/10.1016/j.ejmech.2021.113244
dc.description.abstractCyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was >100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells
dc.identifier.citationEuropean Journal of Medicinal Chemistry, 2021; 214(113244):1-15
dc.identifier.doi10.1016/j.ejmech.2021.113244
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/11541.2/146986
dc.language.isoen
dc.publisherElsevier
dc.relation.fundingCancer Research UK
dc.rightsCopyright 2021 Elsevier Masson SAS
dc.source.urihttps://doi.org/10.1016/j.ejmech.2021.113244
dc.subjectanti-cancer agents
dc.subjectapoptosis
dc.subjectCDK9 inhibitor
dc.subjectchronic lymphocytic leukaemia
dc.titleStructure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916487298101831

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