Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease.

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD. Treatment of PKD-derived cells with this compound not only reduces PAK4 steady-state protein levels and regulates β-catenin signaling, but also inhibits nicotinamide phosphoribosyl transferase, the rate-limiting enzyme in a key NAD salvage pathway. KPT-9274 can attenuate cellular proliferation and induce apoptosis associated with a decrease in active (phosphorylated) PAK4 and β-catenin in several Pkd1-null murine cell lines, with a less pronounced effect on the corresponding phenotypically normal cells. Additionally, KPT-9274 shows inhibition of cystogenesis in an ex vivo model of cyclic AMP-induced cystogenesis as well as in the early stage Pkd1flox/flox:Pkhd1-Cre mouse model, the latter showing confirmation of specific anti-proliferative, apoptotic, and on-target effects. NAD biosynthetic attenuation by KPT-9274, while critical for highly proliferative cancer cells, does not appear to be important in the slower growing cystic epithelial cells during cystogenesis. KPT-9274 was not toxic in our ADPKD animal model or in other cancer models. Thus, this small molecule inhibitor could be evaluated in a clinical trial as a viable therapy of ADPKD.

• Authors: Vicki J Hwang, Xia Zhou, Xiaonan Chen, Josephine Trott, Omran Abu Aboud, Kyuhwan Shim, Lai Kuan Dionne, Kenneth J Chmiel, William Senapedis, Erkan Baloglu, Moe R Mahjoub, Xiaogang Li, Robert H Weiss
• Journal: Kidney international (Kidney Int) Vol. 92 Issue 4 Pg. 922-933 (10 2017) ISSN: 1523-1755 [Electronic] United States
• PMID: 28545714 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Acrylamides
• Aminopyridines
• CTNNB1 protein, mouse
• Cytokines
• KPT-9274
• Pkhd1 protein, mouse
• Receptors, Cell Surface
• TRPP Cation Channels
• beta Catenin
• polycystic kidney disease 1 protein
• NAD
• Nicotinamide Phosphoribosyltransferase
• nicotinamide phosphoribosyltransferase, mouse
• Pak4 protein, mouse
• p21-Activated Kinases

Topics

• Acrylamides (pharmacology, therapeutic use)
• Aminopyridines (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Epithelial Cells
• Female
• Humans
• Kidney (cytology)
• Male
• Mice
• Mice, Transgenic
• NAD (metabolism)
• Nicotinamide Phosphoribosyltransferase (metabolism)
• Organ Culture Techniques
• Phosphorylation
• Polycystic Kidney, Autosomal Dominant (drug therapy, pathology)
• Receptors, Cell Surface (genetics)
• Signal Transduction (drug effects)
• TRPP Cation Channels (genetics)
• beta Catenin (metabolism)
• p21-Activated Kinases (metabolism)