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Novel LKB1-AMPK Activator for Therapeutic Use in Polycystic Kidney Disease

This invention consists of a novel compound and method for treating Polycystic Kidney Disease utilizing a novel liver kinase B1 (LKB1) activator to stimulate AMP-activated protein kinase (AMPK), leading to inhibition of mTOR-mediated cellular proliferation and chloride-dependent fluid secretion, key components of cyst growth.


The present invention addresses the need for a new PKD therapy by the design, synthesis and development of a novel LKB1 activator to 1) stimulate AMPK phosphorylation of tuberin, leading to inhibition of mTOR and cell proliferation, and 2) stimulate AMPK inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel to block fluid secretion by cyst-lining cells.


Polycystic Kidney Disease (PKD) is the most frequently inherited kidney disorder and affects nearly 600,000 Americans and as many as 12 million people worldwide. The disease causes aberrant cell proliferation and chloride-dependent fluid secretion, which result in the formation and enlargement of renal cysts. As the disease progresses, the kidneys become massively enlarged, resulting in the progressive decline in renal function due to extensive nephron loss and replacement of adjacent parenchyma with fibrosis, ultimately leading to renal insufficiency. Currently, there is no approved clinical therapy directed at the cellular defect that is responsible for PKD.


The mammalian Target of Rapamycin (mTOR) pathway is elevated in cyst-lining epithelial cells and contributes to cell proliferation. This invention modulates the mTOR pathway by stimulating AMPK, an energy sensor that inhibits mTOR signaling, cell growth, cell proliferation, and chloride-dependent fluid secretion. Instead of directly targeting AMPK, the invention regulates LKB1, a tumor suppressor and upstream activator of AMPK. This novel approach is superior to other methods because in addition to acting on AMPK, LKB1 is involved in the regulation of energy metabolism, nutrient sensing, glucose homeostasis, and cell growth. Therefore, agents that target LKB1 function will be substantially more effective in their mode of action to inhibit cyst growth in PKD.


In addition to PKD, novel LKB1 activators of this invention may be used to treat other diseases associated with aberrant activity of the mTOR pathway, including cancer, obesity, neurological disorders, and alcohol-related chronic diseases.

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University of Kansas

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Pending Patent

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