A5000833342- Protein Degradation and Inhibitors
- Prostate Cancer Treatment and Research
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Advanced Breast Cancer Therapies
- Hormonal and reproductive studies
- Histone Deacetylase Inhibitors Research
- Estrogen and related hormone effects
- CAR-T cell therapy research
- Nonmelanoma Skin Cancer Studies
- Liver physiology and pathology
- HER2/EGFR in Cancer Research
- Chromatin Remodeling and Cancer
- Nail Diseases and Treatments
- Lung Cancer Research Studies
- Cutaneous Melanoma Detection and Management
- Organ Transplantation Techniques and Outcomes
- Plant Pathogens and Fungal Diseases
- Neuroendocrine Tumor Research Advances
- Pluripotent Stem Cells Research
- Pancreatic function and diabetes
- Mass Spectrometry Techniques and Applications
- Neuroblastoma Research and Treatments
- Xenotransplantation and immune response
Arvinas (United States)
2015-2024
Doylestown Hospital
2019-2024
Yale University
2018-2019
United States Department of Agriculture
2010
Beltsville Agricultural Research Center
2009-2010
Agricultural Research Service
2010
Abstract The androgen receptor is a major driver of prostate cancer and inhibition its transcriptional activity using competitive antagonists, such as enzalutamide remains frontline therapy for management. However, the majority patients eventually develop drug resistance. We propose that targeting degradation via Proteolysis Targeting Chimeras (PROTACs) will be better therapeutic strategy signaling in cells. Here we perform head-to-head comparison between currently approved antagonist...
259 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often relatively short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis...
Abstract Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become central strategy in the treatment ER+ advanced However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. Experimental Design: A medicinal chemistry campaign identified...
Abstract ARV-471, an estrogen receptor (ER) alpha PROTAC, is a hetero-bifunctional molecule that facilitates the interactions between and intracellular E3 ligase complex, leading to ubiquitylation subsequent degradation of receptors via proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with half-maximal concentration (DC50) ˜ 2 nM. PROTAC-mediated decreases expression classically-regulated ER-target genes (PR, GREB1, TFF) inhibits proliferation ER-dependent...
Abstract ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between and intracellular E3 ligase complex, leading to ubiquitylation subsequent degradation of receptors via proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with half-maximal concentration (DC50) ~ 1 nM. mediated decreases expression classically regulated ER-target genes inhibits proliferation ER-dependent (MCF7,...
Abstract Prostate cancer is the second leading cause of death in men United States. The androgen receptor (AR) plays critical roles both early disease and advanced prostate cancer. Current therapeutic approaches targeting androgen/AR axis are initially effective, but castration resistant (CRPC) inevitably develops. CRPC tightly linked with increased AR activity via gene overexpression, amplification, gain-of-function mutations. To address these mechanisms AR-dependent tumor growth, we have...
<div>Abstract<p>Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone enzalutamide) are standard treatments for metastatic hormone-sensitive cancer castration-resistant cancer. However, continual evolution during progression can result in <i>AR</i> alterations mutation, amplification, splicing) cause tumors to become resistant these therapies. Bavdegalutamide (ARV-110) a PROteolysis TArgeting...
Abstract The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis TArgeting Chimera...
Abstract Prostate cancer is the second leading cause of death in men United States. The androgen receptor (AR) plays critical roles both early disease and advanced prostate cancer. Current therapeutic approaches targeting androgen/AR axis are initially effective, but castration resistant (CRPC) inevitably develops. CRPC linked with increased AR activity via gene overexpression, amplification, gain-of-function mutations. To address these mechanisms AR-dependent tumor growth, we have developed...
Abstract Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone enzalutamide) are standard treatments for metastatic hormone-sensitive cancer castration-resistant cancer. However, continual evolution during progression can result in AR alterations mutation, amplification, splicing) cause tumors to become resistant these therapies. Bavdegalutamide (ARV-110) a PROteolysis TArgeting Chimera (PROTAC) protein degrader...
<p>Supplementary Figure S2 shows the effect of bavdegalutamide on neomorphic substrates</p>
<p>Supplementary Figure S3 shows the effect of bavdegalutamide on SALL4</p>
<p>Supplementary Figure S4 shows maintenance of animal body weights during treatment with bavdegalutamide or enzalutamide in prostate cancer mouse models</p>
<p>Supplementary Figure S1 shows the effect of bavdegalutamide on AR versus AR-V7</p>
273 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis TArgeting Chimera...
381 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis TArgeting Chimera...
267 Background: The transition from localized prostate cancer to metastatic disease often involves modulation of the Androgen Receptor (AR). During progression, patients progressing on enzalutamide or abiraterone therapy exhibit amplified AR, increased intra-tumoral androgen production AR mutations leading promiscuity other ligands. Therefore, is still principal driver disease. Methods: A novel approach block signaling specifically target for degradation. To this end, we have developed...
Two cell lines, PICM-19H and PICM-19B, were derived from the bipotent PICM-19 pig liver stem line assessed for their potential application in artificial devices (ALD). The study included assessments of growth rate density culture, morphological features, serum protein production, gamma-glutamyltranspeptidase (GGT) activity hepatocyte detoxification functions, i.e., inducible P450 activity, ammonia clearance, urea production. was by temperature selection at 33-34 degrees C. After each...
<div>AbstractPurpose:<p>Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER<sup>+</sup>)/human epidermal growth factor 2 negative (HER2<sup>−</sup>) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become central strategy in the treatment ER<sup>+</sup> advanced However, suboptimal ER inhibition and resistance resulting from <i>ESR1</i> mutation...
Abstract Progression of prostate cancer in patients treated with anti-androgen therapy usually involves several mechanisms enhanced Androgen Receptor (AR) signaling, including increased intratumoral androgen synthesis, AR expression and mutations. We have developed a protein degradation technology called PROTACs (PROteolysis TArgeting Chimera), which uses bi-functional molecules that simultaneously bind target choice an E3 ligase. PROTACs, via induced proximity, cause ubiquitination the...
Abstract ER-positive breast cancers comprise approximately 70-80% of all newly diagnosed cases. Downregulation or degradation ER is a treatment approach currently used in the clinic to target estrogen receptor signaling. Faslodex, only clinically-approved ER-downregulator, administered as monthly intramuscular injection with limiting pharmaceutical properties. Reasoning that an orally-available degrader would be beneficial patients, we have leveraged our experience targeted protein generate...
Abstract The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during transition from a localized to metastatic disease. Most patients initially respond inhibitors AR pathway, but response is often short-lived. majority progressing on enzalutamide or abiraterone exhibit genetic alterations in locus, either form amplifications point mutations gene. Given these mechanisms resistance, our goal eliminate protein using PROteolysis TArgeting Chimera...