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Chemoproteomic probes for targeted profiling of oncogenic kinase activity

Award Number: R21EB037152
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Chemoproteomic probes for targeted profiling of oncogenic kinase activity - PROJECT SUMMARY Circulating tumor cells (CTCs) are shed from solid tumors into the bloodstream, offering a minimally invasive method to monitor disease progression and treatment response. However, due to their rarity and heterogeneity, isolation and characterization of these liquid biomarkers is extremely challenging. These technical hurdles have hindered functional studies of CTCs, particularly of proteins that drive and regulate aberrant tumor cell phenotype. Advances in chemoproteomics has enabled activity-based kinase profiling of intact cancer cells and tissues using cell-deliverable affinity-based peptide probes (cAfBPs). cAfBPs are artificial peptides with a tripartite structure: a) a recognition sequence that is selectively phosphorylated by the target kinase, b) a bioconjugation handle for attachment of a secondary reporter, and c) a protein transduction domain that triggers rapid cellular uptake via endocytosis. This strategy overcomes challenges associated with phosphosite-specific detection of endogenous proteins or cell homogenate-based systems. However, current cAfBPs target both neoplastic and healthy cells, necessitating sample pre-enrichment. Additionally, successful cAfBP delivery to the cell cytosol requires not only stimulation of cell uptake via endocytosis but also non- cytotoxic release from the endosome. Endosomal escape is a crucial step but major obstacle to efficient delivery of cAfBPs that reduces probe performance. This necessitates the analysis of large numbers of cells to generate reliable data, which is not feasible with limited clinical samples. Our long-term goal is to develop improved bioanalytical tools for minimally invasive monitoring of kinase activity for functional biomarker-based risk stratification and therapy selection. In this Trailblazer application, we will develop next-generation cAfBPs capable of stimulating selective uptake by tumor cells (Aim 1) and efficient trafficking to the cell cytoplasm for phosphorylation (Aim 2). In Aim 1, we will design and characterize a panel of cAfBPs containing membrane transduction domains with organotropic or pan-cancer properties. The cell-type selectivity, uptake, and reporter performance of each probe will be characterized. In Aim 2, we will improve trafficking of cAfBPs to the cytosol for phosphorylation using chimeric domains capable of both membrane translocation and endosomal disruption. We will quantify the signal-to-noise ratio, variability, and other performance metrics for each probe in a cell-based kinase kinetics assay. These contributions are expected to be significant because the proposed work would lay the foundation for functional analysis of key signaling pathways during cancer progression. Additionally, the ability to monitor kinase activity in CTCs will enable future clinical studies to exploit vulnerabilities unique to the dissemination phase.


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: 2026 ( Subtotal = $641,300 )
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	4/27/2026	NEW	$641,300
														Subtotal = $641,300

Grand Total All Awards = $641,300

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Chemoproteomic probes for targeted profiling of oncogenic kinase activity

Award Number: R21EB037152

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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