4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

Cho, Young Shin; Borland, Maria; Brain, Christopher T.; Chen, Christine H.-T.; Cheng, Hong; Chopra, Rajiv; Chung, Kristy; Groarke, James M.; He, Guo Wei; Hou, Ying; Kim, Sunkyu; Kovats, Steven; Lu, Yuele; O’Reilly, Marc; Shen, Junqing; Smith, Troy; Trakshel, G M; Vögtle, Markus; Xu, Mei Ying; Xu, Ming; Sung, Moo Je

doi:10.1021/jm100571n

Cited by 75 publications

(47 citation statements)

References 56 publications

(37 reference statements)

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“…Moreover, phosphorylation of Thr172 in the T-loop does not result in the activation of the enzyme bound to cyclin D1. Furthermore, there are several 3.10 1JOW CDK6 -Vcyclin -9-cyclopentyl-N-(5-piperazin-1-ylpyridin-2-yl)pyrido [4,5]pyrrolo[1,2-d]pyrimidin-2-amine 109 2.90 4TTH CDK6 -Vcyclin -Aminopurvalanol 114 2.80 2F2C CDK6 -Vcyclin -Fisetin 117 2.90 1XO2 CDK6 -Vcyclin -PD0332991 114 3.00 2EUF CDK6 -Kcyclin -p18 INK4c 118 2 111 2.70 4EZ5 CDK6 -1H-benzimidazol-2-yl(1H-pyrrol-2-yl)methanone 111 2.31 4AUA CDK6 -4-[3-(1-methylethyl)-1H-pyrazol-4-yl]-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine 119 2.60 3NUP CDK6 -4-[5-chloro-3-(1-methylethyl)-1H-pyrazol-4-yl]-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine 119 2.70 3NUX CDK6 -p16 INK4a 83 3.40 1BI7 CDK6 -p19 INK4d 74,83 1.90 1BLX 2.80 1BI8 lines of evidence showing that CDK4 might not even be phosphorylated by CAK. 77,78 The INK4 family of CDK inhibitors (CDKIs) which include p16 INK4a , p15 INK4b , p18 INK4c , and p19 INK4d are specific to CDK4 and CDK6.…”

Section: Structural Features and Regulationmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Section: Structural Features and Regulationmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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“…Previously reported structural studies with selective inhibitors bound to CDK6 propose an aromatic sp2 nitrogen in proximity to His100 (His92 in CDK4) as an important determinant for selectivity over other kinases. 16,18,22 Analysis of the structural information in Figure 1 suggested that replacing the benzimidazole with 7-azabenzimidazole would provide an opportunity to test this hypothesis. Indeed, the 7-azabenzimidazole analogue 3 was the first compound to exhibit greater than 10-fold selectivity for CDKs 4 and 6 over CDKs 1 and 2.…”

Section: * S Supporting Informationmentioning

confidence: 99%

“…These results indicated a comparable or improved selectivity profile relative to currently published CDK4/6 selective inhibitors. 16,18 A critical aim of this project was to generate compounds with a high degree of selectivity for CDK4/6 over CDK1/2. During the optimization process, certain modifications were made to the molecule, not solely to increase CDK4/6 potency but to drive the high selectivity over CDK1/2.…”

Section: * S Supporting Informationmentioning

confidence: 99%

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors

Cho¹,

Angove²,

Brain³

et al. 2012

ACS Med. Chem. Lett.

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Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

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“…It indicates that selective CDK4/6 inhibitors potentially have a larger therapeutic window compared with pan-CDK inhibitors [5]. Selectivity of the CDK-inhibitors isimportant for their anticancer pharmacological activity [3].…”

Section: Introductionmentioning

confidence: 99%

“…The substituents at the parent compound which replaced are chlorine (R 2 ) and isopropyl (R 1 ) at the pyrazole ring. Substitution at R 1 position affects its hydrophobic interaction toward CDKs and substitution at R 2 can affect its CDK4 inhibition activity [5].…”

Section: Introductionmentioning

confidence: 99%

Docking of Potent Anticancer Agents; 4-(Pyrazol-4yl)-Pyrimidine Derivatives as Selective Cyclin-Dependent Kinase 4/6 Inhibitors

Akrimah¹,

Tjahyono²,

Musadad³

2013

IJCEA

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Abstract-Cyclin-dependent kinases (CDKs) are regulatory protein kinases which involved in cell cycle control. Many CDK inhibitors have been studied for anticancer potential. Here we conducteda docking studyof 4-(pyrazol-4-yl)-pyrimidine derivatives as CDK1/2 and CDK4/6 inhibitors. Selectivity is an important aspect regarding the anticancer effect. In this computational research, we analyzed the interactionof 4-(pyrazol-4-yl)-pyrimidine derivatives with their receptors, CDK4/6 and CDK2. We compared the docking result of the parent compound, the most selective, and the least selective compound. Docking of the three compounds wasperformed using software Arguslab CDK 4.0.1 to assess the interaction withthereceptors.Three docking parameters were analyzed; Gibbs free energy(∆G), atoms and residue of receptor involved in hydrogen bonding, and the bonding length. All three compounds had value of ΔG <0, indicated that the interaction between the ligand and receptor was spontaneous. However, none of these parameters and descriptors values could explain the selectivity order of the three compounds.Index Terms-Anticancer, CDK inhibitor, computational chemistry, docking, pyrazolo pyrimidine derivatives.

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4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

Cited by 75 publications

References 56 publications

Targeting CDK6 in cancer: State of the art and new insights

Targeting CDK6 in cancer: State of the art and new insights

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors

Docking of Potent Anticancer Agents; 4-(Pyrazol-4yl)-Pyrimidine Derivatives as Selective Cyclin-Dependent Kinase 4/6 Inhibitors

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