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Pharmacological Inhibitors of Nedd4 ubiquitin ligase as anticancer therapeutics

Award Number: R01GM115632
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: 07/01/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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Pharmacological Inhibitors of Nedd4 ubiquitin ligase as anticancer therapeutics - DESCRIPTION (provided by applicant): Protein ubiquitination is a fundamental biological process that regulates all aspects of human biology. Covalent modification of proteins with polyubiquitin chains tags them for proteasomal degradation, while monoubiquitination regulates endocytosis, signal transduction, nuclear import, and gene transcription. To this end, ubiquitin ligase enzymes (~600 known) represent a vast and completely unexplored area of druggable genome. The complexity and diversity of ubiquitin ligases rivals that of three other large families of enzymes: kinases (~500), proteases (~600), and GPCRs (~800). There are 25 FDA approved kinase inhibitor drugs, ~30 FDA approved protease inhibitor drugs, and about 30% of all medications target GPCRs. In stark contrast, there are only 3 FDA approved drugs that target ubiquitin ligases: teratogenic compounds thalidomide, and its analogues lenalidomide and pomalidomide. Significantly, germline and somatic mutations of E3 ligase genes are linked to many human diseases such as cancers, autoimmune diseases, neurodegenerative diseases, and hypertensive disorders. Therefore E3 ligases have recently emerged as prominent targets for basic research and drug discovery. In this proposal, we focus our efforts on developing small molecule inhibitors of HECT E3 ligase Nedd4-1, which is an essential gene in mice and is a positive regulator of IGF-1 and insulin cell growth pathways, pathways that increase the risk and promote the growth of human cancers. Specific aims are as follows (1) To discover covalent inhibitors of Nedd4-1. We used an irreversible tethering technology, to identify two first-in-class covalent inhibitors of Nedd4-1 enzyme, and visualized their binding mode using X-ray crystallography. We propose to investigate biochemical mechanism of action of identified Nedd4-1 inhibitors, (2) conduct structure-activity relationship (SAR) studies of identified Nedd4 inhibitors, (3) to conduct cell based studies of Nedd4-1 inhibitors to show that they inhibit IGF-1/Insulin cell growth pathways in cells. In summary, the proposed research program outlines new concepts to discover covalent small molecule inhibitors of HECT E3 ubiquitin ligase Nedd4-1. The proposed research program will serve as a foundation to initiate novel research directions to discover and optimize small molecule probes targeting other HECT E3 ligases (28 known).


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: 2023 ( Subtotal = -$7,789 )
2023	2019	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	6	11/9/2022	NON-COMPETING CONTINUATION	-$7,789
														Subtotal = -$7,789

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	6	7/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $302,175 )
2019	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	6	6/7/2019	NON-COMPETING CONTINUATION	$302,175
														Subtotal = $302,175

Issue Date FY: 2018 ( Subtotal = $302,175 )
2018	2018	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	5	6/25/2018	NON-COMPETING CONTINUATION	$302,175
														Subtotal = $302,175

Issue Date FY: 2017 ( Subtotal = $304,409 )
2017	2017	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	004	4	6/13/2017	NON-COMPETING CONTINUATION	$301,352
2017	2016	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	002	2	5/12/2017	NON-COMPETING CONTINUATION	-$1,167
2017	2016	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	001	3	2/7/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$265,851
2017	2016	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	2	2/6/2017	NON-COMPETING CONTINUATION	-$262,794
2017	2016	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	003	3	5/12/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,167
														Subtotal = $304,409

Issue Date FY: 2016 ( Subtotal = $286,879 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	2	6/21/2016	NON-COMPETING CONTINUATION	$286,879
														Subtotal = $286,879

Issue Date FY: 2015 ( Subtotal = $287,748 )
2015	2015	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	1	6/29/2015	NEW	$287,748
														Subtotal = $287,748

Grand Total All Awards = $1,475,597

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Pharmacological Inhibitors of Nedd4 ubiquitin ligase as anticancer therapeutics

Award Number: R01GM115632

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: 07/01/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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