Small-Molecule CFTR Inhibitors Slow Cyst Growth in Polycystic Kidney Disease

Abstract

Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTR inh -172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation. These compounds also inhibited cyst number and growth by Ͼ80% in an embryonic kidney cyst model involving 4-d organ culture of embryonic day 13.5 mouse kidneys in 8-Br-cAMP-containing medium. Subcutaneous delivery of tetrazolo-CFTR inh -172 and Ph-GlyH-101 to neonatal, kidney-specific PKD1 knockout mice produced stable, therapeutic inhibitor concentrations of Ͼ3 M in urine and kidney tissue. Treatment of mice for up to 7 d remarkably slowed kidney enlargement and cyst expansion and preserved renal function. These results implicate CFTR in renal cyst growth and suggest that CFTR inhibitors may hold therapeutic potential to reduce cyst growth in PKD.

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

“…85 PKA-induced phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane opens the channel and allows the flow of chloride ions down an electrochemical gradient into the cyst, generating increased transepithelial electron activity that, in turn, drives sodium ions through paracellular pathways. The role of CFTR in PKD is supported by whole-cell patch-clamp studies of cyst-derived epithelial cells, inhibition of fluid secretion by CFTR antisense oligonucleotides, inhibition of cyst growth in in vitro and in vivo models of cystogenesis, [86][87][88][89][90] and the milder cystic phenotype in patients affected by both ADPKD and cystic fibrosis. [91][92][93][94] However, an additional patient with coexisting ADPKD and cystic fibrosis progressed to ESRD after a lung transplant, possibly because of cyclosporin toxicity, and the disease severity of bpk CFTR double mutant mice was not less than the disease severity of bpk mice, a rapidly progressive model of PKD.…”

The Therapeutic Potential of Small-molecule Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− Channel

“…8 These data argue persuasively that BPO-27 is an excellent lead compound for testing in animal models of ADPKD. 123 raises the possibility that CFTR inhibitors might need to be given in combination with a small-molecule that inhibits cAMP-stimulated cell proliferation, a key element in the pathogenesis of ADPKD. 40 Third, cyst growth occurs slowly, over decades in ADPKD patients.…”

Novel Therapies for Polycystic Kidney Disease

“…CFTR inhibition is another recent focus of research for agents that inhibit renal cystic disease. Small molecule inhibitors of CFTR inhibited the development of PKD in a rodent model [65,66]. PPAR-gamma activators have been shown to inhibit vasopressin mediated chloride transport via CFTR [67] and have been shown to inhibit renal cystic disease in rat models of PKD [68][69][70].…”