Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-<i>N</i>-aryl-4,5-dihydrothiazolo[4,5-<i>h</i>]quinazolin-8-amines as Ring-Constrained 2-Anilino-4-(thiazol-5-yl)pyrimidine Cyclin-Dependent Kinase Inhibitors

McIntyre, Neil A.; McInnes, Campbell; Griffiths, G.; Barnett, Anna; Kontopidis, George; Slawin, Alexandra M. Z.; Jackson, Wayne; Thomas, Mark; Zheleva, Daniella; Wang, Shudong; Blake, David G.; Westwood, Nicholas J.; Fischer, Peter M.

doi:10.1021/jm901660c

Cited by 28 publications

(13 citation statements)

References 42 publications

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“…Profiling of CCT068127 against a panel of ~ 30 recombinant human kinases was performed as previously described (McIntyre et al ., ; Wang et al ., ; Wilson et al ., ).…”

Section: Methodsmentioning

confidence: 99%

Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

et al. 2018

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Deregulation of the cyclin‐dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimized from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X‐ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 treatment results in decreased retinoblastoma protein (RB) phosphorylation, reduced phosphorylation of RNA polymerase II, and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT068127 shows greatest similarity to other small‐molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2 family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer.

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“…Profiling of CCT068127 against a panel of ~ 30 recombinant human kinases was performed as previously described (McIntyre et al ., ; Wang et al ., ; Wilson et al ., ).…”

Section: Methodsmentioning

confidence: 99%

Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

et al. 2018

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“…McIntyre et al prepared another type of CDK inhibitor based on pyrimidine and thiazole units ( Scheme 68 c). 229 In several cases, N -aryl-2-aminopyrimidine intermediates 322 were accessed via enaminone and arylguanidine condensation. When this strategy failed, Pd-catalyzed coupling of primary aminopyridines 321 and aryl bromides was used instead, adapting conditions previously reported by Yin and co-workers.…”

Section: Heteroanilinesmentioning

confidence: 99%

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

2016

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Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

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“…A large number of scaffolds have been proposed which bind at the adenosine 5'-triphosphate (ATP) binding pocket of the protein (for a selection see Refs. [25][26][27][28][29]). We consider a series of O 6substituted guanines (Table 1) which probe the ATP-ribose pocket [27].…”

Section: Proteinsmentioning

confidence: 99%

Free enthalpies of replacing water molecules in protein binding pockets

Riniker

Barandun

Diederich

et al. 2012

J Comput Aided Mol Des

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Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate the displacement of water molecules by an apolar probe in the binding pocket of two proteins, cyclin-dependent kinase 2 and tRNA-guanine transglycosylase, using the method of enveloping distribution sampling (EDS) to obtain free enthalpy differences. In both cases, a ligand core is placed inside the respective pocket and the remaining water molecules are converted to apolar probes, both individually and in pairs. The free enthalpy difference between a water molecule and a CH(3) group at the same location in the pocket in comparison to their presence in bulk solution calculated from EDS molecular dynamics simulations corresponds to the binding free enthalpy of CH(3) at this location. From the free enthalpy difference and the enthalpy difference, the entropic contribution of the displacement can be obtained too. The overlay of the resulting occupancy volumes of the water molecules with crystal structures of analogous ligands shows qualitative correlation between experimentally measured inhibition constants and the calculated free enthalpy differences. Thus, such an EDS analysis of the water molecules in the binding pocket may give valuable insight for potency optimization in drug design.

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Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as Ring-Constrained 2-Anilino-4-(thiazol-5-yl)pyrimidine Cyclin-Dependent Kinase Inhibitors

Cited by 28 publications

References 42 publications

Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

Free enthalpies of replacing water molecules in protein binding pockets

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