A5046694271- Protein Degradation and Inhibitors
- Advanced Breast Cancer Therapies
- Histone Deacetylase Inhibitors Research
- Amino Acid Enzymes and Metabolism
- Peptidase Inhibition and Analysis
- Metabolism and Genetic Disorders
- Cancer Research and Treatments
- Nitric Oxide and Endothelin Effects
- Chromatin Remodeling and Cancer
- HER2/EGFR in Cancer Research
- Adenosine and Purinergic Signaling
- Prion Diseases and Protein Misfolding
- CAR-T cell therapy research
- Macrophage Migration Inhibitory Factor
- Crystal structures of chemical compounds
- Chemical Synthesis and Analysis
- Alkaline Phosphatase Research Studies
- Parathyroid Disorders and Treatments
- Click Chemistry and Applications
- Bone health and treatments
- Receptor Mechanisms and Signaling
- Food Quality and Safety Studies
- Biological Activity of Diterpenoids and Biflavonoids
- Vitamin K Research Studies
Arvinas (United States)
2018-2024
Institute for Diabetes Discovery
2013-2019
Yale University
1998-2019
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,...
Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s 223 509 nM, respectively, is active recombinant cellular assay overexpressing (CHO cells). It 28% orally bioavailable significantly reduces infarct size rat...
Cytokine macrophage migration inhibitory factor-2 (MIF-2 or D-dopachrome tautomerase) is a recently characterized second member of the MIF cytokine superfamily in mammalian genomes. MIF-2 shares pro-inflammatory and tumorigenic properties with clinical target (MIF-1), but precise contribution to immune physiology pathology unclear. Like MIF-1, has intrinsic keto-enol tautomerase activity mediates biological functions by engaging cognate, common family receptor CD74. Evidence that catalytic...
Rickets and osteomalacia are characteristic features of the Hyp mouse model human X-linked hypophosphatemia. mice demonstrate elevated circulating osteocalcin levels, as well altered regulation by 1,25(OH)2D3. Whether this abnormality is intrinsic to osteoblast, or mediated in vivo milieu, has not been established. We therefore characterized production its 1,25(OH)2D3 primary cultures murine osteoblasts examined messenger RNA response mouse-derived osteoblasts. Cell viability optimal when...
<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 ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive resistant xenograft models has shown significant promising clinical benefit late-line ER-positive breast cancer patients. Innate acquired drug resistance limits the response durability of many therapies. To identify potential mechanisms ARV-471, we generated...
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...
<p>Supplementary Tables S1-S4 and Figures S1-S16</p>
<p>Extended Methods</p>
<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...
<p>Extended Methods</p>
<p>Supplementary Tables S1-S4 and Figures S1-S16</p>