ATP‐Noncompetitive Inhibitors of CDK–Cyclin Complexes

Orzáez, Mar; Gortat, Anna; Mondragón, Laura; Bachs, Oriol; Pérez‐Payá, Enrique

doi:10.1002/cmdc.200800185

Cited by 19 publications

(11 citation statements)

References 54 publications

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“…Luminescence (RLU) [27,28]. Thus, whether these two new compounds directly modulate the cell cycle by acting as specific CDK inhibitors remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

et al. 2011

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Two novel dichlorophenyl urea compounds, SR4 and SR9, were synthesized in our laboratory and evaluated for anti-cancer activities. Specifically, we investigated the antiproliferative properties of these new compounds on promyelocytic HL-60 leukemia cells by analyzing their effects on cell differentiation, cell cycle progression and apoptosis. SR4 and SR9 were both cytotoxic to HL-60 cells in a dose-and time-dependent manner, with IC(50) of 1.2 μM and 2.2 μM, respectively, after 72 h treatment. Both compounds strongly suppressed growth of HL-60 cells by promoting cell cycle arrest at the G0/G1 transition, with concomitant decrease in protein levels of cyclins D1 and E2 and cyclin-dependent kinases (CDK 2 and CDK 4), and increased protein expression of CDK inhibitors p21(WAF1/Cip1) and p27(Kip1). In addition, either compounds induce cell differentiation as detected by increased NBT staining and expression of CD11b and CD14. Treatment with SR compounds also promoted mitochondrial-dependent apoptosis as confirmed by Annexin V-FITC double staining, DNA fragmentation, increased expression of caspase 3, 7 and 9, cytochrome c release, PARP degradation, and collapse in mitochondrial membrane potential (ΔΨ(MT)). Collectively, these results provide evidence that SR4 and SR9 have the potential for the treatment of human leukemia and merit further investigation as therapeutic agents against other types of cancer.

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“…Luminescence (RLU) [27,28]. Thus, whether these two new compounds directly modulate the cell cycle by acting as specific CDK inhibitors remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

et al. 2011

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“…The challenge now is to develop specific kinase inhibitors for other therapeutic indications where an urgent need for effective treatment exists 4. The overlap between molecular pathways, involved in cancer and neurodegeneration,5 opens the door for the use of protein kinase inhibitors as novel therapeutic approaches for neurodegenerative diseases 6–8.…”

Section: Introductionmentioning

confidence: 99%

Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases

Pérez

Gil

Martı́nez

2011

Medicinal Research Reviews

133

131

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Following the discovery of the human kinome, protein kinases have become the second most important group of drug targets as they can be modulated by small ligand molecules. Moreover, orally active protein kinase inhibitors have recently reached the market and there are many more in clinical trials. The lack of treatments for neurodegenerative diseases has increased human and financial efforts in the search for new therapeutic targets that could provide new effective drug candidates. The importance of kinases in the molecular pathway of neuronal survival is under study, but different key pathways have been described. New roles for the old casein kinases 1 and 2, currently known as protein kinases CK1 and CK2, have recently been discovered in the molecular pathology of different neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. The search for specific inhibitors of these enzymes has become an important challenge for the treatment of these devastating diseases. The role of these two kinases in the molecular pathology of different neurodegenerative diseases together with different chemical families that are able to more or less specifically inhibit CK1 and CK2 are discussed in this review. © 2010 Wiley Periodicals, Inc. Med Res Rev 31:924‐954, 2011

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“…Research has also focused on inhibitors that do not compete with ATP. This mechanisms, represented primarily by pharmacologically active peptides, has been summarized by Orzaez, Cirillo and Abate, 21,22 Also, few small molecules have been described. 23 This manuscript reviews the latest advances on CDK inhibitors design since 2011 (ATP and ATP noncompetitive), with an overview of the chemical structures, relevant structure-activity relationships (SAR) and development status with emphasis on CDK4 and CDK6 inhibitors and other CDK inhibitors under clinical evaluation.…”

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confidence: 98%