CDK/GSK-3 inhibitors as therapeutic agents for parenchymal renal diseases
2007; Elsevier BV; Volume: 73; Issue: 6 Linguagem: Inglês
10.1038/sj.ki.5002731
ISSN1523-1755
AutoresS. H. Obligado, Oxana Ibraghimov‐Beskrovnaya, Anna Żuk, Laurent Meijer, Peter J. Nelson,
Tópico(s)Wnt/β-catenin signaling in development and cancer
ResumoDrug discovery to lessen the burden of chronic renal failure and end-stage renal disease remains a principle goal of translational research in nephrology. In this review, we provide an overview of the current development of small molecule cyclin-dependent kinase (CDK)/glycogen synthase kinase-3 (GSK-3) inhibitors as therapeutic agents for parenchymal renal diseases. The emergence of this drug family has resulted from the recognition that CDKs and GSK-3s play critical roles in the progression and regression of many kidney diseases. CDK/GSK-3 inhibitors suppress pathogenic proliferation, apoptosis, and inflammation, and promote regeneration of injured tissue. Preclinical efficacy has now been demonstrated in mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, polycystic kidney diseases, diabetic nephropathy, and several forms of acute kidney injury. Novel biomarkers of therapy are aiding the process of drug development. This review will highlight these advancements in renal therapeutics. Drug discovery to lessen the burden of chronic renal failure and end-stage renal disease remains a principle goal of translational research in nephrology. In this review, we provide an overview of the current development of small molecule cyclin-dependent kinase (CDK)/glycogen synthase kinase-3 (GSK-3) inhibitors as therapeutic agents for parenchymal renal diseases. The emergence of this drug family has resulted from the recognition that CDKs and GSK-3s play critical roles in the progression and regression of many kidney diseases. CDK/GSK-3 inhibitors suppress pathogenic proliferation, apoptosis, and inflammation, and promote regeneration of injured tissue. Preclinical efficacy has now been demonstrated in mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, polycystic kidney diseases, diabetic nephropathy, and several forms of acute kidney injury. Novel biomarkers of therapy are aiding the process of drug development. This review will highlight these advancements in renal therapeutics. Many drugs used in the renal clinic today originated from their empiric administration to patients with parenchymal renal diseases, despite limited knowledge of disease pathogenesis or molecular drug targets. Seminal clinical observations several decades ago of therapeutic responses from nitrogen mustard,1.Chasis H. Goldring W. Baldwin D.S. The effect of nitrogen mustard on renal manifestations of human glomerulonephritis.J Clin Invest. 1950; 29: 804PubMed Google Scholar steroids,2.Luetscher Jr, J.A. Deming Q.B. Treatment of nephrosis with cortisone.J Clin Invest. 1950; 29: 1576-1587Crossref PubMed Scopus (33) Google Scholar and cyclophosphamide3.Moncrieff M.W. White R.H. Oggs C.S. Cameron J.S. Cyclophosphamide therapy in the nephrotic syndrome in childhood.BMJ. 1969; 1: 666-671Crossref PubMed Scopus (69) Google Scholar in various nephritic and nephrotic renal lesions laid the early foundation for the ongoing empiric use of immunomodulatory drugs to treat many kidney diseases. Recent 'top-down' translational research4.Butcher E.C. Berg E.L. Kunkel E.J. Systems biology in drug discovery.Nat Biotechnol. 2004; 22: 1253-1259Crossref PubMed Scopus (493) Google Scholar to better understand how these drugs may confer efficacy, however, continue to uncover unexpected mechanisms of drug action,5.Wada T. Pippin J.W. Marshall C.B. et al.Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2-related family proteins.J Am Soc Nephrol. 2005; 16: 2615-2625Crossref PubMed Scopus (161) Google Scholar,6.Xing C.Y. Saleem M.A. Coward R.J. et al.Direct effects of dexamethasone on human podocytes.Kidney Int. 2006; 70: 1038-1045Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar underscoring recurring themes in drug discovery: efficacy often results from the integrative rather than the singular action of drugs, and the specificity of drug action is contextual and differs depending on how the molecular targets of drugs promote or resolve any particular disease. Here, we discuss the development of small molecule cyclin-dependent kinase (CDK)/glycogen synthase kinase-3 (GSK-3) inhibitors (CGIs) as therapeutic agents for parenchymal renal diseases. In contrast to discoveries through 'top-down' translational research, the growing interest in CGIs has come via the 'bottom-up' recognition4.Butcher E.C. Berg E.L. Kunkel E.J. Systems biology in drug discovery.Nat Biotechnol. 2004; 22: 1253-1259Crossref PubMed Scopus (493) Google Scholar in molecular nephrology that CDKs and GSK-3s are integrally involved in the pathogenesis and repair of many forms of renal injury. Because these paralogous kinases enter into several biologic processes both within and outside the kidney,7.Malumbres M. Barbacid M. Mammalian cyclin-dependent kinases.Trends Biochem Sci. 2005; 30: 630-641Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar, 8.Knockaert M. Greengard P. Meijer L. Pharmacological inhibitors of cyclin-dependent kinases.Trends Pharmacol Sci. 2002; 23: 417-425Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar, 9.Jope R.S. Johnson G.V. The glamour and gloom of glycogen synthase kinase-3.Trends Biochem Sci. 2004; 29: 95-102Abstract Full Text Full Text PDF PubMed Scopus (1329) Google Scholar, 10.Cohen P. Goedert M. GSK3 inhibitors: development and therapeutic potential.Nat Rev Drug Discov. 2004; 3: 479-487Crossref PubMed Scopus (670) Google Scholar, 11.Meijer L. Flajolet M. Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3.Trends Pharmacol Sci. 2004; 25: 471-480Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 12.Frame S. Zheleva D. Targeting glycogen synthase kinase-3 in insulin signalling.Expert Opin Ther Targets. 2006; 10: 429-444Crossref PubMed Scopus (52) Google Scholar, 13.Dugo L. Collin M. Thiemermann C. Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation.Shock. 2007; 27: 113-123Crossref PubMed Scopus (95) Google Scholar, 14.Romagnani P. Lasagni L. Mazzinghi B. et al.Pharmacological modulation of stem cell function.Curr Med Chem. 2007; 14: 1129-1139Crossref PubMed Scopus (43) Google Scholar CGIs share with many other renal therapeutic agents the propensity for promiscuity in achieving efficacy.15.Nelson P.J. Shankland S.J. Therapeutics in renal disease: the road ahead for antiproliferative targets.Nephron Exp Nephrol. 2006; 103: e6-e15Crossref PubMed Scopus (10) Google Scholar,16.Soos T.J. Meijer L. Nelson P.J. CDK/GSK-3 inhibitors as a new approach for the treatment of proliferative renal diseases.Drug News Perspect. 2006; 19: 325-328Crossref PubMed Scopus (27) Google Scholar This is also evidenced by the ongoing development of CGIs for use in many other diseases, including cancer, diabetes, cardiovascular and neurodegenerative disorders, several viral and parasitic infections, systemic inflammatory syndromes, and in regenerative medicine.7.Malumbres M. Barbacid M. Mammalian cyclin-dependent kinases.Trends Biochem Sci. 2005; 30: 630-641Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar, 8.Knockaert M. Greengard P. Meijer L. Pharmacological inhibitors of cyclin-dependent kinases.Trends Pharmacol Sci. 2002; 23: 417-425Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar, 9.Jope R.S. Johnson G.V. The glamour and gloom of glycogen synthase kinase-3.Trends Biochem Sci. 2004; 29: 95-102Abstract Full Text Full Text PDF PubMed Scopus (1329) Google Scholar, 10.Cohen P. Goedert M. GSK3 inhibitors: development and therapeutic potential.Nat Rev Drug Discov. 2004; 3: 479-487Crossref PubMed Scopus (670) Google Scholar, 11.Meijer L. Flajolet M. Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3.Trends Pharmacol Sci. 2004; 25: 471-480Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 12.Frame S. Zheleva D. Targeting glycogen synthase kinase-3 in insulin signalling.Expert Opin Ther Targets. 2006; 10: 429-444Crossref PubMed Scopus (52) Google Scholar, 13.Dugo L. Collin M. Thiemermann C. Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation.Shock. 2007; 27: 113-123Crossref PubMed Scopus (95) Google Scholar, 14.Romagnani P. Lasagni L. Mazzinghi B. et al.Pharmacological modulation of stem cell function.Curr Med Chem. 2007; 14: 1129-1139Crossref PubMed Scopus (43) Google Scholar The CDK and GSK-3 families of serine/threonine kinases are closely related phylogenetically,17.Manning G. Whyte D.B. Martinez R. et al.The protein kinase complement of the human genome.Science. 2002; 298: 1912-1934Crossref PubMed Scopus (6234) Google Scholar,18.Caenepeel S. Charydczak G. Sudarsanam S. et al.The mouse kinome: discovery and comparative genomics of all mouse protein kinases.Proc Natl Acad Sci USA. 2004; 101: 11707-11712Crossref PubMed Scopus (248) Google Scholar and studies in chemical proteomics19.Bach S. Bondel M. Meijer L. Evaluation of CDK Inhibitors' Selectivity: from Affinity Chromatography to Yeast Genetics.vol. 5. CRC Press, Taylor & Francis, 2006: 103-119Google Scholar,20.Guiffant D. Tribouillard D. Gug F. et al.Identification of intracellular targets of small molecular weight chemical compounds using affinity chromatography.Biotechnol J. 2007; 2: 68-75Crossref PubMed Scopus (52) Google Scholar uncovered their overlapping sensitivity to several chemically diverse small molecules.21.Meijer L. Thunnissen A.M. White A.W. et al.Inhibition of cyclin-dependent kinases GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000; 7: 51-63Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar, 23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 24.Bach S. Knockaert M. Reinhardt J. et al.Roscovitine targets, protein kinases and pyridoxal kinase.J Biol Chem. 2005; 280: 31208-31219Crossref PubMed Scopus (302) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Twenty CDKs (CDK-1 through CDK-13 plus seven CDK-like kinases for which cyclin-binding partners have not been identified) and two GSK-3s (GSK-3α and GSK-3β) exist in the mammalian kinome and share high structural similarity at their ATP-binding and catalytic domains.17.Manning G. Whyte D.B. Martinez R. et al.The protein kinase complement of the human genome.Science. 2002; 298: 1912-1934Crossref PubMed Scopus (6234) Google Scholar, 18.Caenepeel S. Charydczak G. Sudarsanam S. et al.The mouse kinome: discovery and comparative genomics of all mouse protein kinases.Proc Natl Acad Sci USA. 2004; 101: 11707-11712Crossref PubMed Scopus (248) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Despite the divergent feature that CDKs but not GSK-3s typically require protein-binding partners (that is, cyclins) to induce kinase activity,7.Malumbres M. Barbacid M. Mammalian cyclin-dependent kinases.Trends Biochem Sci. 2005; 30: 630-641Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar,8.Knockaert M. Greengard P. Meijer L. Pharmacological inhibitors of cyclin-dependent kinases.Trends Pharmacol Sci. 2002; 23: 417-425Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar both families are inhibited by several of the same CGIs.21.Meijer L. Thunnissen A.M. White A.W. et al.Inhibition of cyclin-dependent kinases GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000; 7: 51-63Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar, 23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 24.Bach S. Knockaert M. Reinhardt J. et al.Roscovitine targets, protein kinases and pyridoxal kinase.J Biol Chem. 2005; 280: 31208-31219Crossref PubMed Scopus (302) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In most cases, this occurs because these 'pan-selective' CGIs compete with ATP for docking at the ATP-binding pocket within CDKs and GSK-3s at similar potencies.21.Meijer L. Thunnissen A.M. White A.W. et al.Inhibition of cyclin-dependent kinases GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000; 7: 51-63Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar, 23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 24.Bach S. Knockaert M. Reinhardt J. et al.Roscovitine targets, protein kinases and pyridoxal kinase.J Biol Chem. 2005; 280: 31208-31219Crossref PubMed Scopus (302) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar These pan-selective CGIs constitute a diverse repertoire of small molecules and include analogues of the purines, pyrimidines, maleimides, flavones, indirubins, along with members of many other chemical classes.21.Meijer L. Thunnissen A.M. White A.W. et al.Inhibition of cyclin-dependent kinases GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000; 7: 51-63Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar, 23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 24.Bach S. Knockaert M. Reinhardt J. et al.Roscovitine targets, protein kinases and pyridoxal kinase.J Biol Chem. 2005; 280: 31208-31219Crossref PubMed Scopus (302) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Modifications around the chemical scaffold of many pan-selective GCIs can logarithmically increase or decrease selectivity for specific CDK and GSK-3 family members.21.Meijer L. Thunnissen A.M. White A.W. et al.Inhibition of cyclin-dependent kinases GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000; 7: 51-63Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar, 23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 24.Bach S. Knockaert M. Reinhardt J. et al.Roscovitine targets, protein kinases and pyridoxal kinase.J Biol Chem. 2005; 280: 31208-31219Crossref PubMed Scopus (302) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar This selectivity is typically demonstrated by in vitro assays utilizing purified kinases, representative substrates, and steady-state concentrations of drug.21.Meijer L. Thunnissen A.M. White A.W. et al.Inhibition of cyclin-dependent kinases GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000; 7: 51-63Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar, 23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 24.Bach S. Knockaert M. Reinhardt J. et al.Roscovitine targets, protein kinases and pyridoxal kinase.J Biol Chem. 2005; 280: 31208-31219Crossref PubMed Scopus (302) Google Scholar, 25.Fischer P.M. CDK versus GSK-3 inhibition: a purple haze no longer?.Chem Biol. 2003; 10: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Whether this selectivity exists during drug administration in vivo, however, is less clear. As with all other small molecule drugs, the pharmacokinetics and pharmacodynamics of each CGI factors importantly into its target selectivity during treatment regimens.26.Lin J.H. Lu A.Y. Role of pharmacokinetics and metabolism in drug discovery and development.Pharmacol Rev. 1997; 49: 403-449PubMed Google Scholar Indeed, in the absence of type I biomarkers to directly detect and monitor the modulation of potential drug targets in vivo, the selectivity of CGIs in vivo is largely extrapolated from in vitro kinase assays, cell culture-based assays, and surrogate/type II biomarkers of drug activity.15.Nelson P.J. Shankland S.J. Therapeutics in renal disease: the road ahead for antiproliferative targets.Nephron Exp Nephrol. 2006; 103: e6-e15Crossref PubMed Scopus (10) Google Scholar,27.Frank R. Hargreaves R. Clinical biomarkers in drug discovery and development.Nat Rev Drug Discov. 2003; 2: 566-580Crossref PubMed Scopus (658) Google Scholar Combined with the fact that CGIs (along with other kinase inhibitors) have not been screened against all known kinases or other nucleotide-interacting proteins, delineating the selectivity of CGIs remains an important focus of research on this drug family.19.Bach S. Bondel M. Meijer L. Evaluation of CDK Inhibitors' Selectivity: from Affinity Chromatography to Yeast Genetics.vol. 5. CRC Press, Taylor & Francis, 2006: 103-119Google Scholar,20.Guiffant D. Tribouillard D. Gug F. et al.Identification of intracellular targets of small molecular weight chemical compounds using affinity chromatography.Biotechnol J. 2007; 2: 68-75Crossref PubMed Scopus (52) Google ScholarTable 1 lists the CGIs that have been studied in renal diseases to date along with their in vitro kinase inhibitory profiles.Table 1Kinase inhibitory profiles (IC50 in μM) for CGIs studied in renal diseasesInhibitoraThe full profile of some CGIs is not known.ClassCDK-1CDK-2CDK-4CDK-5CDK-7CDK-9GSK-3α/βRefs.6-Bromo-indirubin-3′-oximeIndole0.320.3100.08——0.005Meijer et al.,23.Meijer L. Skaltsounis A.L. Magiatis P. et al.GSK-3-selective inhibitors derived from Tyrian purple indirubins.Chem Biol. 2003; 10: 1255-1266Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar Polychronopoulos et al.28.Polychronopoulos P. Magiatis P. Skaltsounis A.L. et al.Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases.J Med Chem. 2004; 47: 935-946Crossref PubMed Scopus (340) Google ScholarFlavopiridolFlavone0.060.150.40.170.30.0060.45Leclerc et al.,22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar Chao et al.29.Chao S.H. Fujinaga K. Marion J.E. et al.Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.J Biol Chem. 2000; 275: 28345-28348Crossref PubMed Scopus (429) Google ScholarOlomoucinePurine77>1003——100Vesely et al.30.Vesely J. Havlicek L. Strnad M. et al.Inhibition of cyclin-dependent kinases by purine analogues.Eur J Biochem. 1994; 224: 771-786Crossref PubMed Scopus (613) Google ScholarPurvalanol BPurine0.0060.006>100.006——>10Leclerc et al.,22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar Gray et al.31.Gray N.S. Wodicka L. Thunnissen A.M. et al.Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.Science. 1998; 281: 533-538Crossref PubMed Scopus (846) Google ScholarR-roscovitinePurine0.450.1314.70.160.490.78130Leclerc et al.,22.Leclerc S. Garnier M. Hoessel R. et al.Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?.J Biol Chem. 2001; 276: 251-260Crossref PubMed Scopus (670) Google Scholar Raynaud et al.32.Raynaud F.I. Whittaker S.R. Fischer P.M. et al.In vitro and in vivo pharmacokinetic–pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202.Clin Cancer Res. 2005; 11: 4875-4887Crossref PubMed Scopus (111) Google ScholarSB216763Maleimide0.55—————0.034Meijer et al.,11.Meijer L. Flajolet M. Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3.Trends Pharmacol Sci. 2004; 25: 471-480Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar Coghlan et al.33.Coghlan M.P. Culbert A.A. Cross D.A. et al.Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.Chem Biol. 2000; 7: 793-803Abstract Full Text Full Text PDF PubMed Scopus (793) Google ScholarSB415286Maleimide0.9—————0.078Meijer et al.,11.Meijer L. Flajolet M. Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3.Trends Pharmacol Sci. 2004; 25: 471-480Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar Coghlan et al.33.Coghlan M.P. Culbert A.A. Cross D.A. et al.Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.Chem Biol. 2000; 7: 793-803Abstract Full Text Full Text PDF PubMed Scopus (793) Google ScholarTDZD-8Thiadiazolidinone>10—————2Meijer et al.,11.Meijer L. Flajolet M. Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3.Trends Pharmacol Sci. 2004; 25: 471-480Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar Martinez et al.34.Martinez A. Alonso M. Castro A. et al.First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease.J Med Chem. 2002; 45: 1292-1299Crossref PubMed Scopus (421) Google ScholarCDK, cyclin-dependent kinase; CGI, cyclin-dependent kinase/glycogen synthase kinase-3 inhibitor; IC50, half-maximal inhibitory concentration; TDZD-8, thiadiazolidinone-8.a The full profile of some CGIs is not known. Open table in a new tab CDK, cyclin-dependent kinase; CGI, cyclin-dependent kinase/glycogen synthase kinase-3 inhibitor; IC50, half-maximal inhibitory concentration; TDZD-8, thiadiazolidinone-8. CDKs and GSK-3s are involved in several essential physiologic responses,7.Malumbres M. Barbacid M. Mammalian cyclin-dependent kinases.Trends Biochem Sci. 2005; 30: 630-641Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar, 8.Knockaert M. Greengard P. Meijer L. Pharmacological inhibitors of cyclin-dependent kinases.Trends Pharmacol Sci. 2002; 23: 417-425Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar, 9.Jope R.S. Johnson G.V. The glamour and gloom of glycogen synthase kinase-3.Trends Biochem Sci. 2004; 29: 95-102Abstract Full Text Full Text PDF PubMed Scopus (1329) Google Scholar, 10.Cohen P. Goedert M. GSK3 inhibitors: development and therapeutic potential.Nat Rev Drug Discov. 2004; 3: 479-487Crossref PubMed Scopus (670) Google Scholar, 11.Meijer L. Flajolet M. Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3.Trends Pharmacol Sci. 2004; 25: 471-480Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 12.Frame S. Zheleva D. Targeting glycogen synthase kinase-3 in insulin signalling.Expert Opin Ther Targets. 2006; 10: 429-444Crossref PubMed Scopus (52) Google Scholar, 13.Dugo L. Collin M. Thiemermann C. Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation.Shock. 2007; 27: 113-123Crossref PubMed Scopus (95) Google Scholar, 14.Romagnani P. Lasagni L. Mazzinghi B. et al.Pharmacological modulation of stem cell function.Curr Med Chem. 2007; 14: 1129-1139Crossref PubMed Scopus (43) Google Scholar and their aberrant activities have been implicated in the pathogenesis of multiple parenchymal renal diseases. Figure 1 depicts several of the major molecular pathways controlled by CDKs and GSK-3s, which have been modulated by GCIs to preserve renal function. Of disease phenotypes, the ability of GCIs to suppress proliferation, apoptosis, and inflammation has received the greatest attention. Because these phenotypes often coexist and synergize to promote progressive injury to the renal parenchyma, CGIs harbor the inherent ability to simultaneously target multiple aspects of disease pathogenesis. Table 2 lists the therapeutic responses to CGIs by various cell types both within and outside the kidney that have been implicated in the development of parenchymal renal diseases.Table 2Therapeutic responses by various cell types implicated in the progression and regression of renal diseasesTherapeutic responseProposed specificity of action of CGIsRefs.Antiproliferative Mesangial cellCell-cycle arrest by inhibiting cell cycle and transcriptional CDKsPippin et al.,35.Pippin J.W. Qu Q. Meijer L. Shankland S.J. Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist.J Clin Invest. 1997; 100: 2512-2520Crossref PubMed Scopus (131) Google Scholar Zoja et al.36.Zoja C. Casiraghi F. Conti S. et al.Cyclin-dependent kinase inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus.Arthritis Rheum. 2007; 56: 1629-1637Crossref PubMed Scopus (38) Google Scholar PodocyteCell-cycle arrest by inhibiting cell cycle and transcriptional CDKsGriffin et al.,37.Griffin S.V. Krofft R.D. Pippin J.W. Shankland S.J. Limitation of podocyte proliferation improves renal function in experimental crescentic glomerulonephritis.Kidney Int. 2005; 67: 977-986Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Nelson et al.,38.Nelson P.J. Gelman I.H. Klotman P.E. Suppression of HIV-1 expression by inhibitors of cyclin-dependent kinases promotes differentiation of infected podocytes.J Am Soc Nephrol. 2001; 12: 2827-2831Crossref PubMed Google Scholar Nelson et al.,39.Nelson P.J. Sunamoto M. Husain M. Gelman I.H. HIV-1 expression induces cyclin D1 expression and pRb phosphorylation in infected podocytes: cell-cycle mechanisms contributing to the proliferative phenotype in HIV-associated nephropathy.BMC Microbiol. 2002; 2: 26Crossref PubMed Scopus (30) Google Scholar Nelson et al.,40.Nelson P.J. D'Agati V.D. Gries J.M. et al.Amelioration of nephropathy in mice expressing HIV-1 genes by the cyclin-dependent kinase inhibitor flavopiridol.J Antimicrob Chemother. 2003; 51: 921-929Crossref PubMed Scopus (50) Google Scholar Gherardi et al.41.Gherardi D. D'Agati V. Chu T.H. et al.Reversal of collapsing glomerulopathy in mice with the cyclin-dependent kinase inhibitor CYC202.J Am Soc Nephrol. 2004; 15: 1212-1222Crossref PubMed Scopus (86) Google Scholar Renal tubular epitheliumCell-cycle arrest by inhibiting cell cycle and transcriptional CDKsBukanov et al.42.Bukanov N.O. Smith L.A. Klinger K.W. et al.Long-lasting arrest of murine polyc
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