Selectivity and potency of cyclin-dependent kinase inhibitors (original) (raw)
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Inhibition of Cellular Proliferation by Drug Targeting of Cyclin- Dependent Kinases
Abnormal cellular proliferation is associated with the pathology of several diseases, including cancer, atherosclerosis and restenosis post-angioplasty. Therefore, antiproliferative therapies may be a suitable approach to treat these disorders. Candidate targets for such strategies include specific components of the cell cycle machinery.
Targeting cyclin dependent kinases in management of human cancer
Innovative Publication, 2016
Uncontrolled proliferation is the hall mark of cancer and abnormal cell cycle regulation in cancer. CDK plays very important role in the control of the cell cycle and its proliferation. CDK2 is the " superstar " among the CDK family.CDK2 has cyclin A and cyclin E in its complex which the cyclin A complex require to progress through S phase regulated by phosphorylation and cyclin E require to transition from the G1 to S phase in cell cycle. Also, the mechanism of binding of CDK2 with its inhibitors as well as the changes of binding mechanisms following conformational variation of CDK2 are compared. Considering this fact, inhibition or disruption of the CDK2/cyclin complexes should be possible to suppress the hyper activation of CDK2 and hold back the infinite cell proliferation. There are main four binding site of CDK inhibitors. Competitive binding sites (site 1), Noncompetitive binding sites (site 2 and 3), Allosteric binding site (site 4). CDK inhibitors are mainly used in cancers including leukemia, melanoma, solid tumors and other types are being targeted.
Recent developments in cyclin-dependent kinase biochemical and structural studies
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2010
The cyclin-dependent kinases (CDKs) have been intensely studied because of their involvement in regulating essential cellular activities that include proliferation and transcription. A series of CDK2-containing structures have informed a general model for the molecular details of CDK activation and regulation. Recent structural studies of other members of the CDK family have lead to a re-appraisal of this model. In this review, we describe alternative CDK-cyclin assemblies taking the recently characterised CDK/cyclin complexes, CDK9/cyclinT1 and CDK4/cyclinD as examples. The differential effects of CDK phosphorylation on CDK activation state and substrate specificity are examined in the light of recent data on CDK2/cyclinA, CDK9/cyclinT, CDK4/cyclinD and Pho85/Pho80. We also present an overview of factors that affect CDK substrate specificity, and, in particular, the contributions that are made by the cyclin subunit. Finally, we review recent results that have helped to unravel the molecular mechanisms underlying the conflicting roles of the Cip/Kip CDK inhibitor family in CDK regulation.
Structural Determinants of CDK4 Inhibition and Design of Selective ATP Competitive Inhibitors
Chemistry & Biology, 2004
molecules that compete with ATP for binding to the kinase. However, an alternative approach currently be-David P. Lane, and Peter M. Fischer Cyclacel Limited ing investigated is to block recruitment of macromolecular substrates to the complex [5]. While there are numer-James Lindsay Place Dundee Technopole ous examples of very potent ATP competitive inhibitors of CDK2 and CDK4 [6-8], very few compounds have Dundee DD1 5JJ United Kingdom progressed past the preclinical stage [9]. Hence, there remains tremendous scope for further development of new classes of CDK inhibitors, especially those that target the individual kinase isoforms specifically. Selec-Summary tive inhibitors might be expected to be generally less cytotoxic and perhaps to exhibit a better side effect A number of selective inhibitors of the CDK4/cyclin profile. CDK4/cyclin D1 has been demonstrated to play D1 complex have been reported recently. Due to the critical roles during initiation of cell division in quiescent absence of an experimental CDK4 structure, the ligand cells (G0/G1 transition) and cell cycle commitment at and protein determinants contributing to CDK4 selecthe restriction point in G1. Furthermore, CDK4 and CDK6 tivity are poorly understood at present. Here, we report are
Cyclin-dependent kinases: inhibition and substrate recognition
Current Opinion in Structural Biology, 1999
Four unresolved issues of cyclin-dependent kinase (CDK) regulation have been addressed by structural studies this year -the mechanism of CDK inhibition by members of the INK4 family of CDK inhibitors, consensus substrate sequence recognition by CDKs, the role of the cyclin subunit in substrate recognition and the structural mechanism underlying CDK inhibition by phosphorylation.
The CDK inhibitors in cancer research and therapy
Journal of Cancer Research and Clinical Oncology
Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.
Pharmacology & Therapeutics, 2002
Components of the cell cycle machinery are frequently altered in cancer. Many of these alterations affect the cyclin-dependent kinases (CDKs) and their regulation. Staurosporine and 7-hydroxystaurosporine (UCN-01) are two natural product kinase inhibitors originally identified as potent protein kinase C inhibitors. Staurosporine is non-selective and too toxic for use in therapy, but UCN-01 shows greater selectivity, and is in clinical trials. We have determined the crystal structures of staurosporine bound to monomeric CDK2 and UCN-01 bound to active phospho-CDK2/cyclin A. Both compounds mimic the hydrogen bonds made by the adenine moiety of ATP, and both exploit the non-polar nature of the adenine-binding site. In the complex with UCN-01, a hydrogen-bonded water molecule is incorporated into the non-polar cavity, which provides a partial polar character in the environment of the 7-hydroxyl group. Comparison of the ATP-binding site of CDK2 with that of other kinases reveals that in Chk1 kinase, a major target for UCN-01 in the cell, one of the surrounding residues, Ala144 in CDK2, is a serine in Chk1, thus providing a possible explanation for the effectiveness of UCN-01 against this kinase. For cells to exit mitosis, the CDKs must be completely inactivated, firstly by the ubiquintin-mediated destruction of the cyclins, followed by dephosphorylation of phospho-Thr160 (in CDK2) catalysed by the kinase-associated phosphatase and protein phosphatase 2C. We describe the structure of phospho-CDK2 in complex with kinase-associated phosphatase, and discuss the substrate recognition promoted by interactions that are remote from the catalytic site.
Highlights of the Latest Advances in Research on CDK Inhibitors
Uncontrolled proliferation is the hallmark of cancer and other proliferative disorders and abnormal cell cycle regulation is, therefore, common in these diseases. Cyclin-dependent kinases (CDKs) play a crucial role in the control of the cell cycle and proliferation. These kinases are frequently deregulated in various cancers, viral infections, neurodegenerative diseases, ischemia and some proliferative disorders. This led to a rigorous pursuit for small-molecule CDK inhibitors for therapeutic uses. Early efforts to block CDKs with nonselective CDK inhibitors led to little specificity and efficacy but apparent toxicity, but the recent advance of selective CDK inhibitors allowed the first successful efforts to target these kinases for the therapies of several diseases. Major ongoing efforts are to develop CDK inhibitors as monotherapies and rational combinations with chemotherapy and other targeted drugs.
The Cyclin-dependent Kinases cdk2 and cdk5 Act by a Random, Anticooperative Kinetic Mechanism
Journal of Biological Chemistry, 2001
cdk2⅐cyclin E and cdk5⅐p25 are two members of the cyclin-dependent kinase family that are potential therapeutic targets for oncology and Alzheimer's disease, respectively. In this study we have investigated the mechanism for these enzymes. Kinases catalyze the transfer of phosphate from ATP to a protein acceptor, thus utilizing two substrates, ATP and the target protein. For a two-substrate reaction, possible kinetic mechanisms include: ping-pong, sequential random, or sequential ordered. To determine the kinetic mechanism of cdk2⅐GST-cyclin E and cdk5⅐GST-p25, kinase activity was measured in experiments in which concentrations of peptide and ATP substrates were varied in the presence of dead-end inhibitors. A peptide identical to the peptide substrate, but with a substitution of valine for the phosphoacceptor threonine, competed with substrate with a K i value of 0.6 mM. An aminopyrimidine, PNU 112455A, was identified in a screen for inhibitors of cdk2. Nonlinear least squares and Lineweaver-Burk analyses demonstrated that the inhibitor PNU 112455A was competitive with ATP with a K i value of 2 M. In addition, a co-crystal of PNU 112455A with cdk2 showed that the inhibitor binds in the ATP binding pocket of the enzyme. Analysis of the inhibitor data demonstrated that both kinases use a sequential random mechanism, in which either ATP or peptide may bind first to the enzyme active site. For both kinases, the binding of the second substrate was shown to be anticooperative, in that the binding of the first substrate decreases the affinity of the second substrate. For cdk2⅐GST-cyclin E the kinetic parameters were determined to be K m, ATP ؍ 3.6 ؎ 1.0 M, K m, peptide ؍ 4.6 ؎ 1.4 M, and the anticooperativity factor, ␣ ؍ 130 ؎ 44. For cdk5⅐GST-p25, the K m, ATP ؍ 3.2 ؎ 0.7 M, K m, peptide ؍ 1.6 ؎ 0.3 M, and ␣ ؍ 7.2 ؎ 1.8. Kinases are a major component of the signal transduction pathways involved in cellular regulation. In addition to their role in maintaining normal homeostasis, there is increasing evidence implicating these enzymes in various diseases, such * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The atomic coordinates and structure factors (code 1JSV) have been deposited in the Protein Data Bank,
Journal of Biological Chemistry, 2009
The cyclin-dependent kinase (Cdk) family is emerging as an important therapeutic target in the treatment of cancer. Cdks 1, 2, 4, and 6 are the key members that regulate the cell cycle, as opposed to Cdks that control processes such as transcription (Cdk7 and Cdk9). For this reason, Cdks 1, 2, 4, and 6 have been the subject of extensive cell cycle-related research, and consequently many inhibitors have been developed to target these proteins. However, the compounds that comprise the current list of Cdk inhibitors are largely ATP-competitive. Here we report the identification of a novel structural site on Cdk2, which is well conserved between the cell cycle Cdks. Small molecules identified by a high throughput in silico screen of this pocket exhibit cytostatic effects and act by reducing the apparent protein levels of cell cycle Cdks. Drug-induced cell cycle arrest is associated with decreased Rb phosphorylation and decreased expression of E2F-dependent genes. Multiple lines of evidence indicate that the primary mechanism of action of these compounds is the direct induction of Cdk1, Cdk2, and Cdk4 protein aggregation.