John Taylor
Professor, Department of Urology
University of Kansas Medical Center

 

 

 

Fragment based screen towards the development of novel PDK inhibitors (2018-19)

Bladder cancer is a common solid malignancy with high rates of recurrence and progression after treatment. Cisplatin remains a mainstay in chemotherapy; however many patients are inherently resistant. Improving cisplatin based therapies is critical to enhancing patient survival in patients with advanced bladder cancer. We have recently identified the pyruvate dehydrogenase kinase (PDK) isozyme family as a critical regulator of cellular response to cisplatin. Inhibition of PDKs, particularly PDK4, results in reduced proliferation, sensitizes cells to cisplatin in vitro and in vivo and activates its target pyruvate dehydrogenase. Unfortunately, current inhibitors of PDKs are largely inappropriate for clinical advancement. The PDK isozyme family provides an ideal platform for Fragment Based Screening of potential inhibitors given the current information present in the field.

The purpose of this project is to perform a fragment based screen for potential PDK binding partners that can be enhanced through
medicinal chemistry as lead candidates for therapeutic development. With the assistance of multiple Core facilities through the Kansas University Protein Structure and Function COBRE, we will identify binding fragments, validate their binding, determine the location of their binding and functionally validate them in vitro. These studies are critical to develop novel, improved PDK inhibitors that can benefit bladder cancer patients in the immediate future.

Specific Aim 1: Identify and validate PDK binding partners using Fragment Based Screening.
Specific Aim 2: Validate functionality of binding fragments in vitro in BCa cell lines.