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Principal Investigator: DAQING WU
Organization: CLARK ATLANTA UNIVERSITY
Fiscal Year: 2024
Award: $56,208
Funding agency: National Cancer Institute
Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PCa), the major
cause of PCa mortality. Unfortunately, in most cases PCa develops docetaxel resistance and continues to
progress, which has no cure. Our recent studies (Theranostics, 2021, May 8; 11: 6873-6890) have provided
strong evidence demonstrating that chemoresistant PCa cells rely on an active EED-EZH2-Stat3-SKP2-
ABCB1/survivin signaling to survive and evade standard chemotherapy. In this R01 project, we hypothesize
that targeting EED-EZH2 interaction with novel EED inhibitors is effective to overcome chemoresistance and
eliminate lethal PCa cells. In Aim 1, we will conduct rational design and chemical optimization of novel EED
inhibitors. A total of 200 new chemical entities will be designed and synthesized. In Aim 2, We will validate the
mechanism of action of potential leads in chemoresistant PCa cells. We will identify the in vitro and in vivo
activities of new EED inhibitors against chemoresistant PCa in multiple, heterogenous preclinical models of
chemoresistant PCa. In Aim 3, we will conduct Good Laboratory Practice (GLP) and non-GLP studies to
evaluate the drug-like properties of lead compounds, including pharmacokinetics, absorption, distribution,
metabolism, and excretion (ADME), single- and repeat-dose toxicity and safety pharmacology. With successful
accomplishment of this project, we expect to identify 1~2 patentable lead compounds and advance them into
further preclinical and clinical development. The overarching goal is to translate our basic research into an
effective and safe treatment for lethal PCa, therefore benefiting patients and improving clinical outcomes.
Terms: <ABC20><ABCB1><ABCB1 gene><APRF protein><ATP-protein phosphotransferase><Acute-Phase Response Factor><Apoptosis Inhibitor 4><Apoptosis Inhibitor Survivin><Baculoviral IAP Repeat-Containing Protein 5><Basic Research><Basic Science><Binding><Biological><Biology><Cancer Patient><Cell Communication and Signaling><Cell Signaling><Center for Cancer Research><Characteristics><Chemicals><Chemoresistance><Clinical><Complex><Death Rate><Development><Development and Research><Disease Progression><Dose><Drug Design><Drug Kinetics><Drug Synthesis and Chemistry><Drugs><Ectoderm><Embryo><Embryonic><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Excretory function><GP170><GeneHomolog><Generalized Growth><Goals><Growth><Homolog><Homologous Gene><Homologue><IL6-response factor><In Vitro><In vivo analysis><Intermediary Metabolism><Interruption><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Kinase Family Gene><Knowledge><LIF-response factor><Lead><MDR-1><MDR1><MDR1 Protein><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Medical><Medication><Metabolic Processes><Metabolism><Mice><Mice Mammals><Molecular Interaction><Multidrug Resistance 1><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Proteins><Murine><Mus><NCI Center for Cancer Research><Oncogenic><Outcome><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><PGY-1 Protein><PGY1><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Pb element><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Phenotype><Polycomb><Pre-Clinical Model><Preclinical Models><Property><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate malignancy><Prostatic Cancer><Protein Kinase><Qualifying><R & D><R&D><Reader><Research><Resistance><S Period><S phase><Safety><Signal Transducer and Activator of Transcription 2><Signal Transducer and Activator of Transcription 3><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Stat2 protein><Stat3 protein><Synthesis Period><Synthesis Phase><Taxotere><Testing><Texas><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Toxicology><Translating><Translational Research><Translational Science><Universities><Work><Xenograft Model><absorption><advanced prostate cancer><analog><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anticancer activity><biologic><biological signal transduction><care for patients><care of patients><caring for patients><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><clinical development><design><designing><developmental><docetaxel><docetaxol><drug development><drug discovery><drug synthesis><drug/agent><epigenetically><excretion><glycogen synthase a kinase><good laboratory practice><heavy metal Pb><heavy metal lead><hormone refractory prostate cancer><hydroxyalkyl protein kinase><improved><in vivo><in vivo evaluation><in vivo testing><inhibitor><innovate><innovation><innovative><interventional strategy><lead optimization><mortality><mortality rate><mortality ratio><new approaches><new chemical entity><novel><novel approaches><novel strategies><novel strategy><ontogeny><pathway><pharmacologic><phosphorylase b kinase kinase><pre-clinical><pre-clinical development><pre-clinical efficacy><pre-clinical safety><preclinical><preclinical development><preclinical efficacy><preclinical safety><prostate cancer cell><prostate cancer model><prostate cancer resistant to androgen><prostate cancer treatment><prostate tumor cell><prostate tumor model><rational design><research and development><resistant><screening><screenings><small molecule><standard of care><survivin><theranostics><therapeutic agent development><therapeutic development><translation research><translational investigation><xenograft transplant model><xenotransplant model>