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Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor

Award Number: R35GM142750
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary /Abstract Intrinsically disordered proteins (IDPs), which lack a fixed three-dimensional structure under physiological conditions, represent ~40% of the human proteome, have crucial functional roles in a variety of biological pathways and biomolecular assemblies and are implicated in a large number of human diseases. As IDPs populate a dynamic conformational ensemble of rapidly interconverting structures in solution, and cannot be represented by a single dominant conformation, or even a small number of substantially populated conformations, they are not suitable targets for conventional structure-based drug design methods. If it becomes possible to target IDPs with small molecule drugs, the druggable proteome will be dramatically expanded and therapeutic interventions may become accessible for currently untreatable diseases The PI’s laboratory utilizes an integrated computational and experimental research strategy to combine state-of-the-art all-atom molecular simulations with experimental measurements from NMR spectroscopy and other biophysical experiments to obtain atomistic descriptions of the dynamic binding mechanisms of IDPs and uses insights form these binding mechanisms to predict and rationally design novel binding interactions. This proposal focuses on applying this integrated computational and experimental approach to elucidate the binding mechanisms of small molecule drug candidates that target that intrinsically disordered domain of the androgen receptor and have entered clinical trials for castration resistant prostate cancer (CRPC). These binding mechanisms will be used to inform the rational design more potent and selective androgen receptor inhibitors and more effective CRPC therapeutics . This proposal describes a remarkable opportunity to draw connections between molecular binding mechanisms studied by molecular simulations and NMR, biological activity observed in cellular assays, and clinical results from human CRPC drug trials. This proposal will initiate a sustainable long-term research effort to combine computational and experimental methods to study the dynamic interactions of IDPs in a variety of cellular and pharmaceutical contexts. This research effort will stimulate the development of robust platforms to integrate computational and experimental methods that will dramatically increase the number of proteins amenable to structural and mechanistic characterization and pharmaceutical targeting and will provide new avenues to therapeutic interventions in diseases associated with aberrant biological interactions of IDPs such as those mediated by biomolecular condensate formation and protein misfolding.


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: 2024 ( Subtotal = $409,560 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	4	6/12/2024	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2023 ( Subtotal = $409,560 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	3	5/30/2023	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2022 ( Subtotal = $409,560 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	2	6/30/2022	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2021 ( Subtotal = $341,681 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	1	9/9/2021	NEW	$341,681
														Subtotal = $341,681

Grand Total All Awards = $1,570,361

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Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor

Award Number: R35GM142750

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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