Summary

Proliferation of specific renal cell types leads to the development of many types of kidney disease. Given the central role that both cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) play in promoting aberrant proliferation within the kidney, these paralogous serine/threonine kinases are being explored as therapeutic molecular targets in proliferative renal diseases. CDK/GSK-3 inhibitors have now demonstrated efficacy in preclinical models of mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, proliferative lupus nephritis and collapsing glomerulopathy. Moreover, they have recently entered human clinical trials in IgA nephropathy. Since the pathogenesis of most proliferative renal diseases is multifactorial, there is the belief that CDK/GSK-3 inhibitors, as inherently promiscuous drugs, may have several modes of action. This is supported by recent studies in systems research delineating the antiinflammatory profile of CDK/GSK-3 inhibitors compared with other immunomodulators. Thus, CDK/GSK-3 inhibitors may emerge as effective drugs for proliferative renal diseases due to their integrative properties across several aspects of disease pathogenesis. This brief mini-review will highlight these issues. © 2006 Prous Science. All rights reserved.

A rapidly growing list of molecular targets to treat proliferative renal diseases has resulted from studies addressing the etiologic and phenotypic basis for the loss of renal function. In the following discussion, we highlight one novel therapeutic strategy to preserve renal function in proliferative renal diseases: by directly inhibiting the activity of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3). These therapeutic molecular targets, and the corresponding family of small molecules that modulate them, are receiving considerable attention in the pharmaceutical industry, furthering the prospect that CDK/GSK-3 inhibitors may emerge as effective therapeutic agents in the near future.

Proliferation: an abnormal phenotype in the kidney

The functional unit of the kidney that maintains fluid, electrolyte and acid/base balances while eliminating many metabolic products from the body is the nephron. In humans, there are approximately 400,000 to 800,000 nephrons per kidney. Unlike some other organs systems, such as the integument, gastrointestinal or hematopoietic systems, all of which exhibit high rates of proliferation due to normal ongoing cell turnover, there is very little cell proliferation within the glomerular or tubular portions of nephrons in a healthy kidney.^1,2 Indeed, the physiologic function of nephrons requires that the renal parenchyma maintain a quiescent, functionally and morphologically differentiated phenotype.³ Thus, aside from renal cells that may infrequently proliferate to repopulate the very low levels of normal cell losses in the mature kidney, or which may undergo reparative proliferation after certain forms of injury (e.g., during recovery from acute tubular necrosis), proliferation of glomerular or tubular cells is a pathogenic phenotype.⁴ Not surprisingly, then, therapeutic strategies that directly target aberrant proliferation of renal parenchyma in order to preserve structure-function relationships required for normal nephron function have been increasingly explored over the last decade with considerable success.⁴

CDK/GSK-3 inhibitors: promiscuous drugs unveiled

The discovery that many small molecules originally developed as CDK inhibitors also block the activity of the phylogenetically and structurally related kinase GSK-3β5-7 underscored the possibility that target promiscuity within this large family of drugs may explain their efficacy in proliferative renal diseases.⁴ Depending on the relative selectivity for specific CDKs or GSK-3 isoforms and the cell-specific functions of each target, CDK/GSK-3 inhibitors may influence many basic cellular processes of different cell types both within and outside the kidney that impact the pathogenesis of proliferative renal diseases.^6-9 CDKs constitute a family of highly conserved protein kinases involved in regulating the cell division cycle, apoptosis, neuronal cell physiology, pain signaling, transcription, RNA splicing and insulin release, among other activities.^6,7 GSK-3 constitutes a family of kinases involved in cell-cycle control, insulin action, apoptosis, neuronal cell death and developmental regulation, among other processes.^8,9 Recognition of this broad biological "target space" for CDK/GSK-3 inhibitors is a key consideration in determining their specificity of action in proliferative renal diseases.⁴ Unlike their well-described indication and advanced clinical development for the treatment of malignant proliferation,¹⁰ in which any contribution from the modulation of CDKs or GSK-3 in nonmalignant cell types is often trivialized (unless it is related to adverse drug events), CDK/GSK-3 inhibitors have demonstrated important new therapeutic activities of relevance to the treat-ment of proliferative renal diseases. As one salient example, we highlight below the emergence of CDK/GSK-3 inhibitors as novel immunomodula-tory drugs.

Efficacy in proliferative renal diseases

CDK/GSK-3 inhibitors are being investigated as therapeutic agents in proliferative renal diseases primarily because of their ability to potently inhibit the activity of cell cycle CDKs, thereby directly inducing cell cycle arrest of proliferating cells.⁴ Table I lists all preclinical testing to date of CDK/GSK-3 inhibitors in various models of proliferative renal diseases as well as in a model of membranous nephropathy. In every instance, CDK/GSK-3 inhibitors ameliorated or reversed the loss of renal function. Based in part on the efficacy demonstrated in the anti-Thy 1.1 model of mesangial proliferative glomerulonephritis, roscovitine recently entered multi-institutional phase II human clinical trials in IgA nephropathy (Seliciclib in IgA Nephropathy Trial by Cyclacel, Limited, Dundee, U.K.). This is the first proposed therapy for IgA nephropathy to enter human clinical trials with clearly defined antiproliferative molecular targets within the renal parenchyma.⁴

Antiinflammatory properties of CDK/GSK-3 inhibitors

Perturbations in immunity and inflammation, particularly towards T helper type 1 deviation,¹¹ play important roles in the pathogenesis of many proliferative renal diseases. One newly recognized therapeutic activity for CDK/GSK-3 inhibitors that is likely to play an important role in treatment regimens stems from their ability to potently influence immune and inflammatory responses. Early studies with hymenialdisine, flavopiridol and indirubin demonstrated that CDK/ GSK-3 inhibitors can directly inhibit nuclear factor κB (NF-κB) signaling, inducing antiinflammatory responses in several different cell types independent of their antiproliferative activity.^12-18 Interestingly, this was recently extended by systems research studies on human endothelial cells, which found that the emergent antiinflammatory properties of CDK/GSK-3 inhibitors (Fig. 1) most closely parallel those of NF-κB inhibitors when compared with a large panel of other drugs.^19,20 While the exact mechanism of action of CDK/GSK-3 inhibitors to explain this drug effect is not fully understood, important preliminary studies in some cell types are providing some answers. For example, CDK/GSK-3 inhibitors can switch the environmental signals received by dendritic cells that would normally induce proinflammatory, T helper type 1 immune responses, into signals that induce tolerogenic, antiinflammatory T helper type 2 immune responses via NF-κB.^21,22 This remarkable modulation appears to stem from the targeting of GSK-3β, rather than from any specific CDK within dendritic cells.²²

Fig. 1. Multi-system BioMAP activity profiles^19,20 for the cyclin-dependent kinases/glycogen synthase kinase-3 (CDK/GSK-3) inhibitors roscovitine and kenpaullone. (A) Roscovitine, a CDK inhibitor only active on GSK-3 at high concentrations, and (B) kenpaullone, a dual CDK/GSK-3 inhibitor, were tested on cultured human endothelial cells challenged by four different inflammatory environments: 3C = T helper type 1 cytokines; 4H = T helper type 2 cytokines; LPS = lipopolysaccharide (LPS) activation of peripheral blood mononuclear cells; Sag = superantigen activation of peripheral blood mononuclear cells. Each system was treated with increasing doses of drug (green = 0.37 µM; yellow = 1.1 µM; orange = 3.3 µM; red = 10 µM) and the change in the expression level (y-axis) of specific endothelial inflammatory markers (x-axis) was determined. There are evident differences in the BioMAPactivity profiles between roscovitine and kenpaullone, indicative of drug family members with differing modes of action and concentration-dependent potencies. However, the overall activities of both of these drugs was most similar to those of nuclear factor κB (NF-κB) inhibitors when compared with a large panel of other immunomodulators.²⁰

Moving forward: biomarkers

Cumulative preclinical research, as well as the recent testing of CDK/ GSK-3 inhibitors in renal clinical settings, suggest that this drug family may emerge as effective agents for the treatment of proliferative renal diseases. However, as these drugs are likely to confer efficacy through several mechanisms, there is a clear need for biomarkers to help determine their combined specificities.⁴ To be exact, there is a need to develop type I biomarkers that can capture the mechanism of action underlying CDK/GSK-3 inhibitors both within and outside the kidney.⁴ Although certain steps in the pathogenesis of individual proliferative renal diseases may be shared in common, others may not, and developing effective biomarkers would aid not only in selecting the most promising CDK/GSK-3 inhibitors, but also in determining which may have broad versus limited applicability in the treatment of various proliferative renal diseases.

Acknowledgments

We thank Ellen Berg, Chief Scientific Officer at BioSeek, Inc., for her contributions to this mini-review. T.J.S. is supported by a Pilot Project Award from the NIH Center for AIDS research grant AI027742. L.M. is supported by a grant from the EEC (FP6-2002-Life Sciences & Health, PRO-KINASE Research Project) and the Canceropole Grand-Ouest. P.J.N. is supported by NIH grant DK065498.

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Timothy J. Soos, is Research Assistant Professor and Peter J. Nelson* is Assistant Professor of Medicine at the Division of Nephrology, New York University School of Medicine, New York, U.S.A.; Laurent Meijer is Director at CNRS, Cell Cycle Group, Station Biologique, Roscoff, Bretagne, France. *Correspondence: Peter J. Nelson, MD, Division of Nephrology NYU School of Medicine, Smilow Research Center, Room 904, 522 First Avenue, New York, NY 10016, U.S.A. Tel.: (212) 263-7681; Fax: (212) 263-7683. E-mail: nelsop02@popmail. med.nyu.edu.

Drug News & Perspectives Vol. 19, No. 6, 2006, pp. 325-328
ISSN 0214-0934 Copyright 2006 Prous Science, S.A. CCC: 0214 0934/2006
DOI: 10.1358/dnp.2006.19.6.985939
http://www.prous.com

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