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.
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.
|Boselli, Monica; Lee, Byung-Hoon; Robert, Jessica et al. (2017) An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons. J Biol Chem 292:19209-19225|
|Lee, Byung-Hoon; Lu, Ying; Prado, Miguel A et al. (2016) USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature 532:398-401|
|Lub, Susanne; Maes, Anke; Maes, Ken et al. (2016) Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells. Oncotarget 7:4062-76|
|Lu, Ying; Lee, Byung-hoon; King, Randall W et al. (2015) Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science 348:1250834|
|de Lange, Job; Faramarz, Atiq; Oostra, Anneke B et al. (2015) Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function. Nat Commun 6:8399|
|King, Randall W; Finley, Daniel (2014) Sculpting the proteome with small molecules. Nat Chem Biol 10:870-4|
|Sackton, Katharine L; Dimova, Nevena; Zeng, Xing et al. (2014) Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 514:646-9|
|Lim, Hui-Jun; Dimova, Nevena V; Tan, Meng-Kwang Marcus et al. (2013) The G2/M regulator histone demethylase PHF8 is targeted for degradation by the anaphase-promoting complex containing CDC20. Mol Cell Biol 33:4166-80|
|Pfaff, Kathleen L; King, Randall W (2013) Determinants of human cyclin B1 association with mitotic chromosomes. PLoS One 8:e59169|
|Sigoillot, Frederic D; Lyman, Susan; Huckins, Jeremy F et al. (2012) A bioinformatics method identifies prominent off-targeted transcripts in RNAi screens. Nat Methods 9:363-6|
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