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Principal Investigator: Michael A Erb
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $570,856
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Histone deacetylases (HAT) are zinc-dependent enzymes that catalyze the removal of acetyl groups from the
epsilon amine of lysine side chains. These proteins have been widely pursued as anti-cancer drug targets, but
therapeutic development has been largely unsuccessful given the essential nature of many HDAC proteins.
Recently, we discovered a synthetic lethal relationship between HDAC1 and HDAC2, which is caused by
recurrent chromosomal deletions that result in hemizygous deletion of HDAC1 in neuroblastoma and HDAC2 in
multiple myeloma. As a result of HDAC1 deletion, neuroblastoma cells are hypersensitive to disruption of
HDAC2, and vice versa in multiple myeloma. Using dTAG-mediated degradation or CRISPR/Cas9-based gene
disruption, we discovered that targeting HDAC1/2 synthetic lethality (e.g. degrading HDAC2 in neuroblastoma
cells with a hemizygous HDAC1 deletion) results in dissociation of the NuRD chromatin remodeler complex, of
which HDAC1/2 are members. Dissociation of the complex results in degradation of NuRD subunits that are
selectively required for neuroblastoma and multiple myeloma survival, suggesting that HDAC1/2 synthetic
lethality can be leveraged to target subunit-specific NuRD vulnerabilities in cancer. We hypothesize that HDAC1
deletions cause the NuRD subunits, HDAC2 / MBD3 / MTA3, to be essential for neuroblastoma, whereas HDAC2
deletions cause vulnerabilities to loss of their paralogs, HDAC1 / MBD2 / MTA2, in multiple myeloma. Here, we
will address this hypothesis and explore the translational potential of these vulnerabilities by developing small-
molecule modulators that target NuRD structure and/or function. In Aim 1, we will (i) Determine whether MBD
and MTA vulnerabilities are caused by HDAC1/2 deletions using CRISPR/Cas9, inducible RNAi, and dTAG-
based approaches in vitro and in vivo, (ii) Reveal whether the loss of NuRD subunits required for cancer cell
survival leads to dissociation and/or degradation of the NuRD complex using unbiased proteomics approaches,
and (iii) Establish if HDAC1/MBD2/MTA2 and HDAC2/MBD3/MTA3 form distinct NuRD sub-complexes as a
result of HDAC2 and HDAC1 deletions, respectively. These experiments will determine if subunit-specific NuRD
vulnerabilities are caused by HDAC1/2 deletions or simply exploited by HDAC1/2 synthetic lethality. In Aim 2,
we will develop small molecules targeting the NuRD complex to exploit NuRD vulnerabilities in genetically
defined cancer sub-types. Specifically, we will: (i) develop paralog-selective PROTACs that distinguish between
HDAC1 and HDAC2, (ii) determine the potential for covalent ligands of MTA3-Cys532 to disrupt NuRD structure
and/or function in MTA3-dependent cancers, and (iii) develop MTA3-targeted PROTACs based on ligands that
covalently engage MTA3-C532. Altogether, successful completion of these aims will determine the mechanisms
underlying NuRD vulnerabilities in cancer and advance novel chemical tools to drug and study them.
Terms: <Abscission><Amines><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Binding><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 technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Drug><Cancers><Cas nuclease technology><Cell Body><Cell Survival><Cell Viability><Cells><Chemicals><Chromatin><Chromatin Structure><Chromosomal Deletion><Chromosome Deletion><Clinic><Clinical><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><Complex><Data><Deacetylation><Dependence><Dissociation><Drug Targeting><Drugs><Enzyme Gene><Enzymes><Excision><Extirpation><Gene Transcription><Genes><Genetic><Genetic Transcription><HD1><HDAC><HDAC Agent><HDAC Proteins><HDAC inhibitor><HDAC1><HDAC1 gene><HDAC2><HDAC2 gene><Histone Deacetylase><Histone Deacetylase 1><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><In Vitro><L-Lysine><Ligands><Lysine><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Modernization><Molecular Interaction><Multiple Myeloma><Nature><Neoplastic Disease Chemotherapeutic Agents><Neuroblastoma><Nucleosomes><Oncology><Oncology Cancer><Output><Partial Monosomy><Pharmaceutical Preparations><Plasma-Cell Myeloma><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><Proteomics><RNA Expression><RNA Interference><RNA Silencing><RNAi><RPD3-Like 1><RPD3L1><Recurrence><Recurrent><Reduced Potassium Dependency 3, Yeast, Homolog-Like 1><Removal><Sequence-Specific Posttranscriptional Gene Silencing><Side><Somatic Cell><Structure><Surgical Removal><Therapeutic><Transcription><Tumor-Specific Treatment Agents><Work><YAF1><Zinc><Zn element><amine><anti-cancer drug><anti-cancer therapeutic><cancer cell><cancer sub-types><cancer subtypes><cancer survival><cancer type><cell type><chromatin remodeling><clinical development><design><designing><drug/agent><experiment><experimental research><experimental study><experiments><fitness><in vivo><inhibitor><malignancy><member><myeloma><myelomatosis><neoplasm/cancer><neuroblastoma cell><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><paralog><paralogous gene><pharmacologic><resection><small molecule><therapeutic agent development><therapeutic development><tool><translational opportunities><translational potential><tumor>