Project Name: Modulating Androgen Receptor with Bifunctional Recruiters

 

Androgen receptor (AR) is a protein that, when activated, stimulates the growth and survival of prostate cancer cells. Many drugs developed to treat prostate cancer aim to prevent this activation, keeping AR in a repressed state. Unfortunately, AR evolves over time and becomes resistant to these therapies, highlighting the need for new approaches to modulate AR.

Cells have enzymes called histone deacetylases (HDACs) that suppress the function of many proteins. If one were able to recruit these HDAC machines to AR, they may repress its function. My research will test this hypothesis by developing molecules to achieve this recruitment, drugs we term bifunctional recruiters. In cells, bifunctional recruiters will act like molecular bridges; contacting AR on one end and HDACs on the other, bringing the two in close proximity.

The goals of my research are to:                                                                                                           

  1. Synthesize a collection of bifunctional recruiters that vary in the type of molecules that bind AR/HDACs as well as the distance between these molecules. This will help identify the optimal features of these molecular bridges.

  2. Assess the ability of bifunctional recruiters to cause recruitment of HDACs to AR. Chromatin immunoprecipiation (ChIP) is one technique that will be employed, providing a picture of which proteins associate with one another on DNA.

  3. Assess the impact of HDAC recruitment on AR-regulated transcription. A hallmark of activated AR is its ability to promote transcription. By monitoring the levels of both natural and artificial reporters, we will assess the effectiveness of our drugs at blocking AR function.

Summer 2018 Update from Dr. Van Dyke: I am completing my fifth year as an Assistant Professor of Chemistry at Fairfield University, a Jesuit University in southeast Connecticut. Our department supports a vibrant undergraduate research culture. I mentor six students, ranging from sophomores to seniors. As a chemical biology group, my lab is interested in applying the tools of chemistry to better understand biological systems. To date, we have developed a method for selectively tagging native enzymes without altering their intrinsic function. This is useful because it will allow us to observe the behavior of disease-causing proteins in their original state. Additionally, our lab has received a two-year grant from the United States Department of Agriculture, in collaboration with the Department of Biology at Fairfield University, to investigate the immunomodulatory properties of eggs. While much is known about the cholesterol and lipid effects of eggs, much remains to be explored about how these bioactive foods affect our body's immune system. This grant and these research projects would not have been possible without the career-boosting postdoctoral fellowship provided by the ACS-MCRF.

 

Summer 2019 Update from Dr. Aaron Van Dyke: This year Dr. Van Dyke was tenured and promoted to Associate Professor of Chemistry at Fairfield University. He is a chemical biologist with specialties in organic synthesis and chemical education. His undergraduate-driven research group utilizes small molecule and proteomic strategies to understand the role of protein signaling in inflammation.

Dr. Van Dyke is the recipient of more than $700,000 in federal research grants from the National Science Foundation and the United States Department of Agriculture, to support this scholarly work. He pioneered the use of digital laboratory notebooks at Fairfield University and has published extensively on digital literacy in peer reviewed-journals, including: Journal of Chemical Education and ACS Chemical Biology. He is the Academic Chair of Fairfield’s Residential College Program and lives on campus in the Ignatian Leadership Residential College. He is an alumnus of the Association of Jesuit Colleges and University’s (AJCU) Ignatian Colleagues Program (ICP) and serves on the selection committee for the Barry M. Goldwater Scholarship.