Rational design and development of novel protein kinase D inhibitors

Description of projects available to graduate students:
This is an interdisciplinary collaborative project that focuses on developing potent and selective protein kinase D (PKD) small molecule inhibitors for in vivo and cellular application. We and others have demonstrated that PKD is a promising novel therapeutic target for cancer. In collaboration with the Drug Discovery Institute and the Department of Chemistry at the University of Pittsburgh, we seek to further our efforts in developing novel small molecule PKD inhibitors. The current focus is on drug-like ATP-competitive inhibitors with in vivo activity. We have generated several lead compounds from our initial screens. The new leads will be subjected to extensive structural modifications to enhance potency and selectivity and will be evaluated for in vivo efficacy in tumor xenograph models. Additionally, using affinity labeled analogs at tools, a major effort will be devoted to identify and solve the 3D structure of the inhibitor binding pocket and/or the PKD protein in complex with the inhibitors through mass spec and crystallography. These efforts will guide structural-based rational design of next generation PKD inhibitors.

Techniques graduate student will learn:
A wide range of interdisciplinary approaches will be used in this project including methods of enzymology, biochemistry, molecular biology, recombinant protein production and purification, mutagenesis, computational modeling, drug screen, structural-based drug design, mass spec, cystallography