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Novel Integrin-Linked Kinase (ILK) Inhibitors for Therapeutic and Diagnostic Uses

This invention features novel compounds and a method of treatment to reduce cyst growth in Polycystic Kidney Disease (PKD). The compounds target a key cellular pathway involved in aberrant proliferation in PKD and other hyperproliferative disorders, including cancer and neurological disorders. Additionally, compounds are synthesized using a unique approach to improve drug efficacy, specificity, solubility and cellular uptake.

PKD is a potentially lethal genetic disease affecting nearly 600,000 Americans and as many as 12 million people worldwide. In PKD, numerous fluid-filled cysts are formed by aberrant proliferation of tubule epithelial cells, resulting in massively enlarged kidneys and a progressive decline in renal function. There is no approved clinical therapy directed at the cellular defect responsible for PKD. The present invention addresses the need for a new PKD treatment by the design, synthesis and development of novel ILK inhibitors using boron chemistry.

HOW IT WORKS:

Integrin-linked kinase (ILK) is a signaling molecule that bridges the communication between the extracellular matrix and cell signaling pathways through cell surface integrins. Using a partial crystal structure of ILK, the inventors designed and synthesized novel boron-containing compounds that bind to specific residues in the kinase pocket of ILK. These compounds target aberrant cell proliferation by reducing ILK activation of Akt/mTOR- and GSK3beta/beta-catenin-mediated signaling, both of which have been implicated in cyst growth in PKD and tumor growth in cancer. Initial drug screenings showed compounds inhibiting cell proliferation in nanomolar concentrations.

BENEFITS: 

Boron-based ILK inhibitors have higher efficacy, increased specificity, reduced toxicity and increased cell permeability compared to commercially available carbon-based ILK inhibitors, such as CPD-22

WHY IT IS BETTER:

Initial drug screenings showed compounds inhibiting cell proliferation in nanomolar concentrations.

OTHER APPLICATIONS:

An effective ILK blocker could be used to treat many conditions, including PKD, cancer, neurological disorder disease, ocular disease, and other hyperproliferative diseases with aberrant ILK activity. These compounds could also be used as novel radiosensitizers for many diseases with drug resistance, or as novel materials for drug delivery and imaging tools.

Additional Details

Owner

University of Kansas

Intellectual Property Protection

Pending Patent



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