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Designing Plk1 Inhibitors through multiscale computational and experimental methods

Award Number: R15GM148942
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: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Designing Plk1 Inhibitors through multiscale computational and experimental methods - Identification of Novel, Selective Plk1 Inhibitors through Molecular Modeling and Fluorescence Polarization Experiments The long-term goal of the proposed study is to identify novel nonpeptide-based selective inhibitors for polo-box domain (PBD) of polo-like kinase 1 (PLK1) that can be used for targeted cancer therapies. Given its major role in mitotic events, PLK1 is a marker for cellular proliferation with a prognostic potential in some types of cancers. A high level of PLK1 expression is associated with a poor prognosis. Studies have shown that the loss of PLK1 expression can induce apoptosis and inhibit growth in many cancer cells while showing an insignificant effect on normal cells in mouse models. On the other hand, PLK2 and PLK3 have been identified as tumor suppressors. Therefore, selective and specific inhibition of PLK1 is a promising therapeutic strategy for a range of cancer types. In our study, the rationale for targeting the PBD as opposed to the kinase catalytic domain (KCD) is that the KCD is conserved among kinases and therefore poses selectivity and toxicity problems. PLK1 inhibitors will be identified in several steps. (1) Small molecules with known binding profiles to PLK1-3 will be studied through molecular dynamics (MD) simulations to gain atomistic insights for the key interactions needed for strong binding profile for PLK1 but not for PLK2-3. (2) COCONUT natural products database and Atomwise company small molecule database will be screened to identify potential inhibitors. The top hit candidates will be studies through MD and ADMETS (absorption, distribution, metabolism, excretion, toxicity and stability) simulations to reduce the number of candidates and finally the top molecules will be studies through steered MD and fluorescence polarization experiments. The proposed study is innovative in many aspects but particularly its unique design for allowing meaningful participation of Deaf and Hard of Hearing undergraduate and high school students. Major outcome of the study is that it is expected to provide a starting point for a drug design pipeline for the PBD of PLK1 and further guide the in vivo experiments and/or clinical considerations.


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: 2025 ( Subtotal = $0 )
2025	2022	GALLAUDET UNIVERSITY	800 FLORIDA AVE NE	WASHINGTON	DC	20002	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	001	1	6/25/2025	NEW	$0
2025	2022	GALLAUDET UNIVERSITY	800 FLORIDA AVE NE	WASHINGTON	DC	20002	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	11/13/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $368,671 )
2022	2022	GALLAUDET UNIVERSITY	800 FLORIDA AVENUE, NE	WASHINGTON	DC	20002	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	9/19/2022	NEW	$368,671
														Subtotal = $368,671

Grand Total All Awards = $368,671

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Designing Plk1 Inhibitors through multiscale computational and experimental methods

Award Number: R15GM148942

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: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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