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Discovery of Novel Peptidic Inhibitors of the Non-Catalytic Function of Focal Adhesion Kinase (FAK)

Award Number: R41CA240124
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2021

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Discovery of Novel Peptidic Inhibitors of the Non-Catalytic Function of Focal Adhesion Kinase (FAK) - PROJECT SUMMARY ABSTRACT Focal Adhesion Kinase (FAK) is a major cancer drug target that is overexpressed in multiple tumor types. FAK is a critical regulator of tumor survival, invasion, proliferation, metastasis, and immune evasion. Current FAK inhibitors that target the ATP-binding pocket of the kinase domain do no effectively inhibit FAK in cancer because FAK also functions as a scaffolding protein. The Focal Adhesion Targeting (FAT) domain of FAK is an interesting alternative drug target due to its requirement for FAK localization, activity, and downstream effects. Disruption and mutation of the FAT domain causes significant effects on tumor cell apoptosis, proliferation, invasion, and metastasis. Specifically, the FAT domain interacts with the alpha helical LD2 and LD4 motifs of Paxillin to promote its biological effects. The structure of the FAT-Paxillin complex has been solved by x-ray crystallography however has been challenging to target with small molecules. In this project, we will use hydrocarbon stapled alpha helical peptides that have the advantage of enhanced proteolytic stability, cell permeability, and potent inhibition of the entire protein interaction interface. We have preliminary data of Stapled Peptide 3 showing low micromolar inhibition of FAK-Paxillin binding and NMR/SPR data validating the binding site of the peptide. In the first specific aim, we will perform structure-activity relationships (SAR) on stapled alpha helical peptides for enhanced binding and competitive inhibition. We will perform SAR on stapled peptides by changing hydrocarbon stapling strategy, modifying N- and C-terminal amino acids, and adding alternative amino acids. In addition, we will utilize molecular modeling to optimize peptide-protein contacts, synthesize stapled peptides of homologous peptide sequences, and characterize biophysical/biochemical properties of stapled peptides. In the second specific aim, we will characterize and optimize lead peptides for cellular effects. We will perform robust assays to measure cell permeability of stapled peptides, characterize peptides for protease resistance and effects on membrane lysis, and test peptides in cellular efficacy assays to assess the effects of stapled peptides on cancer cells. In the third specific aim, we will test lead peptides with in vitro DMPK assays and preliminary in vivo efficacy models. We will characterize peptides using plasma binding, metabolic stability, and CYP inhibition/assays. We will also test lead peptides in mouse xenograft models alone and in combination with chemotherapy. In all, these specific aims will be used to discover peptide inhibitors of FAK non-catalytic function that can be the basis for future clinical development.


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 = -$3,556 )
2022	2019	FAKNOSTICS, LLC	475 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Cancer Biology Research	000	1	7/21/2022	NEW	-$3,556
														Subtotal = -$3,556

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	FAKNOSTICS, LLC	2914 E MINNEZONA AVE	PHOENIX	AZ	85015	MARICOPA	USA	Cancer Biology Research	000	1	12/9/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $289,594 )
2019	2019	FAKNOSTICS, LLC	2914 E MINNEZONA AVE	PHOENIX	AZ	85015	MARICOPA	USA	Cancer Biology Research	000	1	8/30/2019	NEW	$289,594
														Subtotal = $289,594

Grand Total All Awards = $286,038

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Discovery of Novel Peptidic Inhibitors of the Non-Catalytic Function of Focal Adhesion Kinase (FAK)

Award Number: R41CA240124

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2021

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