A5030624410- Protein Degradation and Inhibitors
- Advanced Breast Cancer Therapies
- Chromatin Remodeling and Cancer
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- Renal cell carcinoma treatment
- CAR-T cell therapy research
- Cancer, Hypoxia, and Metabolism
- Multiple Myeloma Research and Treatments
- HER2/EGFR in Cancer Research
- Meat and Animal Product Quality
- Cytokine Signaling Pathways and Interactions
- Quinazolinone synthesis and applications
- Fibroblast Growth Factor Research
- Melanoma and MAPK Pathways
- Lung Cancer Research Studies
- Cancer Mechanisms and Therapy
- Angiogenesis and VEGF in Cancer
Arvinas (United States)
2022-2025
Bayer (United States)
1996-2006
Bayer (Germany)
2002
The mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated in cancer and inactivation results a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving high degree of selective inhibition likely essential to afford acceptable therapeutic index, realizing this objective challenging due the homology with paralog. Herein we report discovery potent...
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...
The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for over closely related paralog BRG1 (SMARCA4). They also selectively impair proliferation H1944 "BRG1-mutant" NSCLC cell line, which lacks functional thus highly dependent on growth, relative to wild-type Calu6 line. In vivo performed...
Abstract Background Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics not known. Methods A typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14 C-A947 (BRM degrader)—was synthesized its was studied by quantitative whole-body autoradiography (QWBA) excision in rats following IV dosing. Bile duct-cannulated (BDC) allowed the elucidation of vivo clearance pathways....
Abstract BPTF is a bromodomain and PHD finger domain-containing protein that serves as scaffolding subunit of the ISWI family member NURF chromatin remodeling complex. Together with interchangeable catalytic subunits SMARCA1 SMARCA5 additional RBBP4, RBBP7, complex catalyzes ATP to slide nucleosomes on DNA, exposing or occluding transcription factor binding sites, leading transcriptional activation repression. Dysregulation BPTF-containing complexes disrupts gene expression contributes...
Abstract BCL6 is a preclinically validated oncogenic driver of DLBCL historically considered to be undruggable. ARV-393, PROteolysis TArgeting Chimera (PROTAC) degrader, directly binds an E3 ubiquitin ligase and induce ubiquitination its subsequent proteasomal degradation. ARV-393’s iterative activity overcomes rapid resynthesis resulting in potent, single-agent tumor regressions many cell- patient-derived xenograft (CDX PDX) models. ARV-393 monotherapy being evaluated phase 1 trial...
Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved recent years, with several of them clinical trials. While most these advances been associated monovalent protein degraders, bivalent PROTACs also entered trials, although progression to market has limited. One the reasons is complex physicochemical properties heterobifunctional PROTACs. A strategy improve pharmacokinetics highly lipophilic compounds, such as PROTACs,...
Abstract ARV-471 is a selective, orally bioavailable PROteolysis-TArgeting Chimera (PROTAC®) small molecule that induces wild-type and mutant estrogen receptor (ER) alpha degradation via the ubiquitin-proteasome system. demonstrates superior ER antitumor activity compared to fulvestrant in endocrine sensitive resistant xenograft models has shown significant promising clinical benefit late-line ER+ breast cancer patients. Dual pathway inhibition combining targeting agents with CDK4/6 or...
<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 KRAS is genomically altered in about one third of all human tumors. Due to its central role oncogenesis, many attempts have been made the last four decades drug mutant KRAS, either directly or indirectly. Despite recent advances targeting using small molecule inhibitors, majority alterations do not yet an existing targeted therapy, and where inhibitors are available, resistance rapidly emerges. Thus, novel approaches drugging needed. Eliminating a protein degradation approach may...
<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>
Abstract The mammalian SWI/SNF helicase SMARCA4 is frequently mutated in cancer and inactivation results a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving high degree of selective inhibition likely essential to afford acceptable therapeutic index, realizing this objective has been challenging due the homology with paralog. Herein we report discovery first potent proteolysis-targeting...