Multiple myeloma (MM) is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. Unfortunately, >97% of MM patients develop resistance or become intolerant to current treatments within a few months/years, after which survival is less than one year. We have developed a class of proteasome inhibitors that regulate the proteasome via a mechanistically distinct, non-competitive, protein:ligand interaction that overcomes resistance and is highly effective in vivo. Little is known about how and where non-competitive inhibitors bind to the proteasome or how they exert their biological activity. In this proposal we will utilize a novel mass spectrometry labeling technology to fill this critical void in our understanding of this alternative mechanism and define its differences from the current paradigm of proteasome inhibition.

Public Health Relevance

Nearly all multiple myeloma patients develop resistance or become intolerant to treatment with proteasome inhibitors within a few months/years, after which survival is less than one year. We have developed a class of proteasome inhibitors that regulate the proteasome via a mechanistically distinct, non-competitive, protein:ligand interaction that overcomes resistance and is highly effective in vivo. This proposal we will utiliz a novel mass spectrometry labeling technology to characterize this alternative mechanism and define its differences from the current paradigm of proteasome inhibition.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA182926-02
Application #
8804249
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Knowlton, John R
Project Start
2014-02-11
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
2
Fiscal Year
2015
Total Cost
$156,119
Indirect Cost
$47,369
Name
Michigan State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824