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Principal Investigator: Dongwen Lyu
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2024
Award: $192,844
Funding agency: National Cancer Institute
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.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATP-Dependent Proteolysis Factor 1><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Gene Caspase 2><Assay><Autophagocytosis><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma-extra large><B-cell lymphoma/leukemia-2><BCL-XL><BCL2><BCL2 gene><BCL2-Like 1><BCL2-Related Gene><BCL2-Related Protein, Long Isoform><BCL2-Related Protein, Short Isoform><BCL2L1><BCL2L1 gene><BCLX><BCLXL><BCLXS><Bcl-2><Binding Sites><Bioassay><Biological Assay><Biological Function><Biological Process><CASP-2><CASP2><CASP2 gene><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Treatment><Cas nuclease technology><Caspase><Caspase Gene><Caspase-2 Gene><Cell Body><Cell Death><Cell-Death Protease><Cells><Chimera><Chimera Protein><Chimera organism><Chimeric Proteins><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Combining Site><Computer Models><Computerized Models><Consumption><Cysteine><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Data><Development><E3 Ligase><E3 Ubiquitin Ligase><FK-506-Binding Protein><FK506 Binding Proteins><FKBP><FKBP Rotamase><Family><Foundations><Fusion Protein><Future><Genes><HDM2><HMG-20><Half-Cystine><High Mobility Protein 20><Human><ICE-like protease><ICH-1 Protease Gene><ICH-1L><ICH-1L/1S><ICH1><Ich-1 protein><In Vitro><Knock-out><Knockout><L-Cysteine><Libraries><Ligands><Lysosomes><MCL-1><MCL1><MCL1 gene><MDM2><MDM2 gene><MDMX protein><Macropain><Macroxyproteinase><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Mdm-2 protein><Mediating><Metabolic Protein Degradation><Modality><Modern Man><Multicatalytic Proteinase><NEDD2><NEDD2 Apoptosis Regulatory Gene><Names><Natural Products><Nedd-2 protein><Oncogene Products><Oncogene Proteins><Oncoprotein MDM2><Oncoproteins><Process><Programmed Cell Death><Property><Prosome><Protac><Proteasome><Proteasome Endopeptidase Complex><Protein Cleavage><Protein Turnover><Proteins><Proteolysis><Proteolysis targeting chimeric><Proteosome><Reactive Site><Regulatory Protein Degradation><Series><Site><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Solid><Structure><System><Tacrolimus Binding Proteins><Targeted DNA Modification><Targeted Modification><Technology><Testing><Therapeutic><Time><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><activity-based protein profiling><analog><anti-cancer><anti-cancer therapy><autophagy><bcl-2 Genes><cancer therapy><cancer-directed therapy><caspase-2><ced9 homolog><chimeras><computational modeling><computational models><computer based models><computerized modeling><cystein protease><cystein proteinase><cysteine endopeptidase><design><designing><developmental><dietary><experiment><experimental research><experimental study><experiments><flexibility><flexible><inhibitor><interest><mdm-2 oncogene protein><mdm2 protein><multicatalytic endopeptidase complex><myeloid cell leukemia 1><myeloid cell leukemia sequence 1><myeloid leukemia cell differentiation protein><name><named><naming><naturally occurring product><necrocytosis><new approaches><novel approaches><novel strategies><novel strategy><p53-Binding Protein MDM2><protein degradation><protein function><proteolysis targeting chimera><recruit><screening><screenings><senolytics><small molecule><success><tool><ubiquitin-protein ligase><weapons>