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Principal Investigator: Brian S J Blagg
Organization: UNIVERSITY OF NOTRE DAME
Fiscal Year: 2024
Award: $423,618
Funding agency: National Cancer Institute
Summary:
Hsp90 is a molecular chaperone that is responsible for the conformational maturation of
signaling proteins associated with all ten hallmarks of cancer, making it a promising
target for the treatment of cancer, as multiple signaling nodes can be simultaneously
derailed as a consequence of Hsp90 inhibition. Moreover, researchers have shown that
Hsp90 inhibitors accumulate in tumors with high differential selectivity, making Hsp90 a
highly sought after target for cancer. Unfortunately, clinical trials with 17 small molecule
inhibitors have led to multiple detriments that have significantly dampened enthusiasm
for Hsp90 inhibitors, as increased levels of Hsp90 were observed in the clinic, which led
to dose-escalating toxicities among other concerns. Consequently, Hsp90 remains a
desirable target for the development of cancer chemotherapeutics, but new approaches
to inhibit the protein machinery are needed that do not induce Hsp90 levels. Through a
number of seminal studies, it has been shown that inhibitors of the Hsp90 C-terminal
domain can segregate Hsp90 inhibition from induction of Hsp90 levels, and therefore,
we propose in this application to optimize these compounds and to perform a number of
pre-IND studies on the best molecules in an effort to move them toward clinical
evaluation.
Terms: <3-D><3-Dimensional><3D><Ablation><Academia><Affinity><After Care><After-Treatment><Aftercare><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Apoptosis><Apoptosis Pathway><Apoptotic><Binding><Binding Sites><C-terminal><CDDP><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Cetuximab><Chaperone><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Client><Clinic><Clinical Evaluation><Clinical Testing><Clinical Trials><Combining Site><Crystallinic Acid><Cysplatyna><Development><Dichlorodiammineplatinum><Dose><Dose Limiting><Drug Industry><Drug Kinetics><Drug resistance><Drug toxicity><Drugs><Engineering><Enzyme Gene><Enzymes><Exhibits><Geldanamycin><Generalized Growth><Genes><Genetic Markers><Growth><HNSCC><HSP 90 inhibition><HSP90 inhibition><Head and Neck Squamous Cell Carcinoma><Heat Shock><Heat-Shock Reaction><Heat-Shock Response><Hepatotoxic effect><Hepatotoxicity><Immune><Immunes><In vivo analysis><Intracellular Communication and Signaling><Investigators><Lead><Ligands><Liver Toxicity><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Metabolic Protein Degradation><Modification><Molecular Chaperones><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><N-terminal><NH2-terminal><Non-Malignant><Novobiocin><Pathway interactions><Patients><Pb element><Peyrone's Chloride><Peyrone's Salt><Pharmaceutic Industry><Pharmaceutical Industry><Pharmaceutical Preparations><Pharmacokinetics><Platinum Diamminodichloride><Population><Pre-Clinical Model><Preclinical Models><Process><Programmed Cell Death><Proliferating><Protein Turnover><Proteins><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Regulatory Protein Degradation><Research Personnel><Researchers><Resistance><SCCHN><Schedule><Seminal><Series><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Solubility><Strains Cell Lines><Streptonivicin><Structure><Therapeutic><Tissue Growth><Toxic effect><Toxic effect on liver cells><Toxicities><Tumor Cell><analog><anti-cancer><anti-cancer therapy><anti-tumor drug><anticancer activity><biological signal transduction><cancer cell><cancer therapy><cancer-directed therapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical development><clinical test><computer based prediction><conformation><conformational><conformational state><conformationally><conformations><cultured cell line><developmental><drug resistant><drug/agent><geldanomycin><gene biomarker><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><head and neck squamous carcinoma><head and neck squamous cell cancer><heat shock protein 90 inhibition><heavy metal Pb><heavy metal lead><hepatic toxicity><hepatoxicity><improved><in vivo><in vivo evaluation><in vivo testing><inhibitor><innovate><innovation><innovative><lead optimization><malignancy><meter><molecular recognition><nano-molar><nanomolar><neoplasm/cancer><neoplastic cell><new anti-cancer agent><new anticancer agent><new anticancer drug><new antineoplastic><new approaches><new cancer drug><next generation><nonmalignant><novel><novel anti-cancer agent><novel anti-cancer drug><novel anticancer agent><novel anticancer drug><novel antineoplastic><novel approaches><novel cancer drug><novel strategies><novel strategy><ontogeny><pathway><polypeptide><post treatment><pre-IND enabling studies><pre-IND experiments><pre-IND studies><predictive modeling><prevent><preventing><process optimization><protein degradation><protein folding><research clinical testing><resistance to Drug><resistant><resistant to Drug><scRNA-seq><segregation><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecular inhibitor><small molecule><small molecule inhibitor><therapeutic target><three dimensional><transcriptome sequencing><transcriptomic sequencing><tumor><tumor growth><tumorigenic>