Microtubule inhibitors, such as taxanes, represent one of the most widely used treatments for cancer. By perturbing the mitotic spindle, taxanes activate the spindle assembly checkpoint (SAC), which subsequently induces mitotic arrest and cell death. However, cancers vary widely in their sensitivity to taxanes, perhaps due to differences in the strength of the checkpoint and efficiency of mitotic arrest. Because the only known function of the SAC is to inhibit the ubiquitin ligase activity of the Anaphase-Promoting Complex/Cyclosome (APC), direct APC inhibitors might be more effective at inducing mitotic arrest, without toxicities associated with microtubule perturbation. Using phenotypic screens in Xenopus cell cycle extracts, combined with biochemical studies to identify targets of active molecules, we have identified two small molecules that inhibit APC dependent proteolysis. This grant application encompasses four major goals. First, to understand, at the atomic level, how TAME and cyclinal interact with their protein targets. Second, to understand the detailed mechanisms by which these compounds perturb APC activity. Third, to understand how these compounds perturb regulation of APC by the SAC. Fourth, to leverage our understanding of the cellular effects of these molecules to identify new classes of APC inhibitors. Through our studies, we hope to establish a definitive mechanistic understanding of how these compounds inhibit APC activity and lay the intellectual and technical groundwork for development of APC inhibitors as drugs to treat cancer.

Public Health Relevance

Microtubule inhibitors, such as taxanes, represent one of the most widely used treatments for cancer, but the responsiveness of different tumors can vary widely. Here we explore a new approach to treating cancer, by directly targeting proteins required for cell division. These compounds can arrest cells in mitosis and induce cell death more effectively than taxanes, providing a new approach for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066492-11
Application #
8598885
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Hamlet, Michelle R
Project Start
2002-05-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$350,799
Indirect Cost
$143,111
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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