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Targeting Protein-Protein Interactions for Disruption of LSD1 (KDM1A) Complexes

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Date
2017
Author
Schwabe, Jennifer Link
Advisor
McCafferty, Dewey G
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Abstract

Lysine-specific demethylase 1 (LSD1/KDM1A) regulates transcriptional events by post-translational modifications of histone H3 tails at residues K4 an K9. This enzyme plays a vast number of roles in both normal cellular functions and diseases states. Increasingly it is appreciated that this enzyme, like most epigenetic regulators, does not function alone, but rather forms a catalytic subunit of much larger protein assemblies that congregate on chromatin to concertedly mediate transcriptional events. LSD1 in particular has been found in many different complexes, in many different tissues and can facilitate both activation and repression events.

Because of these roles, LSD1 is viewed as a potential therapeutic target. Significant effort has recently led to the development of highly selective and potent active-site inhibitors. These inhibitors have particularly shed light on the cancer-promoting activities of LSD1 in acute myeloid leukemia and small cell lung carcinoma. However, one failing of these strategies is that active site inhibition is incapable of differentiating between the multitude of functions LSD1 performs. We sought to address this issue by instead developing first-generation tools to explore protein-protein interaction disruption as an alternative strategy for inhibiting the enzyme.

To this end, we have carefully examined a well-characterized interaction between LSD1 and the scaffolding protein CoREST. Using this interaction as a template, we developed a probe we show can compete with CoREST for interaction with LSD1. Furthermore, we generated cell permeable versions of this probe and examined the effects in a model of breast cancer. We find that our probe can selectively inhibit estrogen signaling, a feat that was not possible with current small molecule inhibition or RNA interference technologies. We therefore we propose that disrupting interactions such as this is an excellent alternative for targeting “undruggable” proteins, but also may also expand the current therapeutic space by granting precise control over the individual functions of proteins.

Type
Dissertation
Department
Chemistry
Subject
Biochemistry
Cellular biology
CoREST
Estrogen Signaling
KDM1A
LSD1
Protein-protein interaction
Permalink
https://hdl.handle.net/10161/14487
Citation
Schwabe, Jennifer Link (2017). Targeting Protein-Protein Interactions for Disruption of LSD1 (KDM1A) Complexes. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/14487.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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