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Drug discovery of N-WASP inhibitors in metastatic breast cancer cell lines

Award Number: SC2GM116712
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: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Drug discovery of N-WASP inhibitors in metastatic breast cancer cell lines - PROJECT SUMMARY In cancer cells, formation of these membrane protrusions called invadopodia is upregulated due to excessive activation of signaling pathways that control actin polymerization. The Wiskott-Aldrich syndrome protein (WASP) family proteins are important regulators of actin polymerization and invadopodia formation. The neural-WASP (N-WASP) is a central regulator of Arp2/3 complex-mediated actin polymerization into invadopodia to initiate cell migration, and thus, cancer metastasis. N-WASP is activated at the cell membrane during invadopodia initiation, thus, implicating N-WASP in the initiation of cell invasion. Therefore, in this research we proposed to synthesize small molecule carbazole derivatives that inhibit the activity of N-WASP and test their potential inhibitory action on metastatic breast cancer cell lines. The new carbazole derivatives will be synthesized through several chemical transformations to produce a short link between the aromatic carbazole and the aliphatic polar segment. Additionally, we will identify, through a virtual screening method, new compounds to be tested in pyrene-actin polymerization assays and analyze its ability to reduce migration by targeting N-WASP activity. The overall goal of this project is to discover and develop new drugs for the treatment of breast cancer metastasis via specific inhibition of N-WASP. The central hypothesis of this proposal is that specific and selective inhibition of N-WASP activity can be effectively used to block breast cancer invasion and metastasis. The new N-WASP inhibitors will be designed based on the available 3-D coordinates of N-WASP structure and docking software. The binding, and inhibitory potential of novel compounds as N-WASP inhibitors will be investigated by their ability to block actin nucleation in cancer cell lysates following EGF stimulation or addition of upstream effectors Cdc42 or PIP2 pyrene-labeled actin polymerization assay. The pharmacological activity of N-WASP inhibitors will be determined on breast cancer invasion and metastasis.


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: 2022 ( Subtotal = -$18,764 )
2022	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	3	11/3/2021	NON-COMPETING CONTINUATION	-$18,764
														Subtotal = -$18,764

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	3	2/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $150,000 )
2019	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	3	7/12/2019	NON-COMPETING CONTINUATION	$150,000
														Subtotal = $150,000

Issue Date FY: 2018 ( Subtotal = $150,000 )
2018	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	2	7/9/2018	NON-COMPETING CONTINUATION	$150,000
														Subtotal = $150,000

Issue Date FY: 2017 ( Subtotal = $150,000 )
2017	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	1	7/31/2017	NEW	$150,000
														Subtotal = $150,000

Grand Total All Awards = $431,236

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Drug discovery of N-WASP inhibitors in metastatic breast cancer cell lines

Award Number: SC2GM116712

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: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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