title: CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle and proliferation. Although no effective therapy for the treatment of PKD is currently available, possible mechanism-based approaches are beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell cycle connection using CDK-inhibitor R-roscovitine showed effective arrest of PKD in jck and cpk models that are not orthologous to human ADPKD. To evaluate whether CDK inhibition approach will translate into efficacy in an orthologous model of ADPKD, we tested R-roscovitine and its derivative S-CR8 in a model with a conditionally inactivated Pkd1 gene (Pkd1 cKO). Similar to ADPKD, Pkd1 cKO mice developed renal and hepatic cysts. Treatment of Pkd1 cKO mice with R-roscovitine and its more potent and selective analog S-CR8 significantly reduced renal and hepatic cystogenesis and attenuated kidney function decline. Mechanism of action studies demonstrated effective blockade of cell cycle and proliferation and reduction of apoptosis. Together, these data validate CDK inhibition as a novel and effective approach for the treatment of ADPKD.
authors.affiliation: Cell Biology, Genzyme, a Sanofi Company, Framingham, MA, USA.
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Moreno
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Natoli
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rogers
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Smith
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000077546:Roscovitine
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; C580576:S-CR8 compound; D000077546:Roscovitine; C089212:protein kinase D; D011493:Protein Kinase C; D018844:Cyclin-Dependent Kinases; D000225:Adenine