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Discovering and Exploiting Selectivity within Tandem Bromodomains

Award Number: R35GM128840
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Discovering and Exploiting Selectivity within Tandem Bromodomains - PROJECT SUMMARY The goals of this research program are to understand how bromodomain ‘reading’ of the epigenetic histone language is regulated by metabolism (Direction 1) and disease-associated missense variants (Direction 2). Our approach is multidisciplinary, focusing on mechanisms and developing novel chemical tools as starting points for drug development (Direction 3). Bromodomains bind acyl-lysines on histones and other nuclear proteins to modulate transcription. The importance of bromodomain-mediated transcription in human disease is well- established. Bromodomain inhibitors are in clinical trials for multiple indications, including cardiovascular disease and cancer. Despite these achievements, several critical questions remain. For example, histone and transcription factor lysine residues are modified by an array of non-acetyl acylations. These acylations are derived from acyl-CoA metabolites, indicating an intricate interplay between the cellular energy states that modulate acyl-CoA levels and bromodomain-mediated transcriptional regulation. Where, when, and how these acylations recruit bromodomains to chromatin for transcriptional regulation is poorly understood. Therefore, we are testing the hypothesis that changes in metabolic flux induce distinct histone acylations that are ‘read’ by specific bromodomains to regulate transcription and inflammation (Direction 1). Bromodomains are also hot spots for cancer-associated missense variants. However, the impacts of these variants on bromodomain- mediated transcriptional regulation are largely unknown. Elucidating the mechanisms through which bromodomain missense variants transcriptionally regulate key cancer signaling pathways will spur the development of novel precision medicine therapeutic approaches. Accordingly, we are testing the hypothesis that bromodomain missense variants with disrupted stability, structure, and dynamics attenuate bromodomain- mediated transcriptional regulation of key cancer signaling pathways (Direction 2). Here, we employ the integrated computational and biophysical pipeline that we developed in the Medical College of Wisconsin Structural Genomics Unit to interrogate disease-associated missense variants from protein structure to integrative transcriptomics. Another critical barrier to progress in bromodomain biology is the lack of inhibitors and chemical probes specifically targeting individual bromodomains. We are overcoming this barrier by developing selective bromodomain inhibitors using a novel fragment NMR screening pipeline we pioneered in the Medical College of Wisconsin Program in Chemical Biology (Direction 3). In line with the NIGMS mission to increase understanding of biological processes and advance knowledge of disease, our mechanistic inquiries into bromodomain-mediated transcriptional regulation, coupled with our development of inhibitors and chemical probes, will distinguish the differential activities of bromodomains in cell and animal models of health and disease. Additionally, our research will identify valuable starting points to develop therapeutics targeting the bromodomain transcriptional regulatory axis in an array of human inflammatory diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $351,000 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	8	1/21/2026	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2025 ( Subtotal = $390,000 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	003	7	8/13/2025	NON-COMPETING CONTINUATION	$39,000
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	002	7	1/15/2025	NON-COMPETING CONTINUATION	$351,000
2025	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	6	11/22/2024	COMPETING CONTINUATION	$0
2025	2022	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	001	5	1/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,000

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	001	6	1/30/2024	COMPETING CONTINUATION	$390,000
2024	2022	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	5	1/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $381,000 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	001	5	8/15/2022	NON-COMPETING CONTINUATION	$231,000
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	4	6/7/2022	SUPPLEMENT FOR EXPANSION	$150,000
														Subtotal = $381,000

Issue Date FY: 2021 ( Subtotal = $231,000 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	4	8/13/2021	NON-COMPETING CONTINUATION	$231,000
														Subtotal = $231,000

Issue Date FY: 2020 ( Subtotal = $320,998 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	2	7/1/2020	SUPPLEMENT FOR EXPANSION	$90,000
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	001	3	8/18/2020	NON-COMPETING CONTINUATION	$230,998
														Subtotal = $320,998

Issue Date FY: 2019 ( Subtotal = $231,000 )
2019	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	2	9/5/2019	NON-COMPETING CONTINUATION	$231,000
														Subtotal = $231,000

Issue Date FY: 2018 ( Subtotal = $368,328 )
2018	2018	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Biomedical Research and Research Training	000	1	8/23/2018	NEW	$368,328
														Subtotal = $368,328

Grand Total All Awards = $2,663,326

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Discovering and Exploiting Selectivity within Tandem Bromodomains

Award Number: R35GM128840

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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