Download Chemical Approaches to Improving Proteasome

Chemical Approaches to Improving Proteasome-Targeted Cancer Therapies
Kyung Bo Kim, Ph.D.
Associate Professor
Department of Pharmaceutical Sciences
University of Kentucky, Lexington, KY
A major focus of our research is the application of chemical tools to improve the proteasometargeted cancer therapies. Proteasome inhibitors such as carfilzomib (Kyprolis®) and bortezomib
(Velcade®) have markedly improved the prognosis of refractory multiple myeloma, but intrinsic
and acquired cancer resistance to proteasome inhibitor therapy remains significant clinical
concerns. Our current research efforts are to explore the resistance mechanisms using novel
chemical tools and to identify novel strategies for overcoming drug resistance. Based on our
initial observations and literature reports by others, we hypothesized that intermediate or hybrid
proteasomes containing a non-standard mixture of proteasome catalytic subunits may play a
role in cancer resistance to carfilzomib or bortezomb. A major obstacle in testing our hypothesis
is the lack of practical ways to determine the subunit composition of a single 20S proteasome
complex in cancer cells. Here, we present the development of two novel, complementary
strategies that employ small molecule probes for determining the subunit composition of
proteasomes in cancer cells. In addition, we aim to develop novel proteasome inhibitors that can
overcome obstacles and limitations associated with the peptide-based proteasome inhibitors,
such as bortezomib and carfilzomib. We will present our efforts to develop novel proteasome
inhibitors with non-peptide scaffolds and a reversible binding mode.