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Development of Caspase Cleavage Targeting Chimeras (CACTACs) for Targeted Protein Cleavage.

Award Number: R21CA286307
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Development of Caspase Cleavage Targeting Chimeras (CACTACs) for Targeted Protein Cleavage. - PROJECT SUMMARY Caspases are a family of cysteine proteases which can cleave proteins containing cleavage sites on the flexible region to trigger cell death through apoptosis or pyroptosis. Recently, bifunctional small molecules, such as proteolysis targeting chimeras (PROTACs), lysosome targeting chimeras (LYTACs), or autophagy targeting chimeras (AUTACs), have emerged as potential therapeutic modalities by hijacking the ubiquitin-proteasome system (UPS), lysosome or autophagy to degrade proteins of interest (POIs). Caspase cleavage is a one-step process that instantly terminate protein function. Here, we discovered that piperlongumine (PL), a dietary natural product, can recruit caspase(s) to cleave Bcl-xL when conjugated with a Bcl-xL/2 inhibitor ABT263. This finding motivated us to further develop bifunctional small molecules for targeted protein cleavage by recruiting caspases, which could be superior to or complementary to the known degraders. We termed this kind of compounds caspase cleavage targeting chimeras (CACTACs). In this proposal, we will apply a series of state-of-the-art technologies to find the caspase(s) recruited by the current PL-based Bcl-xL CACTAC and confirm the mechanism of action. In addition, we will build a Halo-FKBP system to further genetically explore the potential of CACTAC-mediated targeted protein cleavage by various caspases. The caspase-cleavage site pairs will be systematically identified to inform the future CACTAC design. We will also further develop new caspase-2 recruiters through PL analog library screening and structure/computer modeling-based optimization. More CACTACs targeting other POIs will be synthesized and tested to expand the application of CACTACs. The CACTAC platform proposed here will offer a revolutionary weapon against oncoproteins for cancer therapy.


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 = $215,984 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	2	6/11/2025	NON-COMPETING CONTINUATION	-$27,595
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	2	11/1/2024	NON-COMPETING CONTINUATION	$194,387
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	002	3	6/11/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$49,192
														Subtotal = $215,984

Issue Date FY: 2024 ( Subtotal = $192,844 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	1	11/29/2023	NEW	$192,844
														Subtotal = $192,844

Grand Total All Awards = $408,828

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Development of Caspase Cleavage Targeting Chimeras (CACTACs) for Targeted Protein Cleavage.

Award Number: R21CA286307

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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