A5021167157- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Cancer-related Molecular Pathways
- CAR-T cell therapy research
- Microgrid Control and Optimization
- PI3K/AKT/mTOR signaling in cancer
- Smart Grid Energy Management
- Power Systems and Renewable Energy
- Melanoma and MAPK Pathways
- Integrated Energy Systems Optimization
- Retinoids in leukemia and cellular processes
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Sphingolipid Metabolism and Signaling
- Acute Myeloid Leukemia Research
- HVDC Systems and Fault Protection
- Receptor Mechanisms and Signaling
- Smart Grid and Power Systems
- Click Chemistry and Applications
- Carbohydrate Chemistry and Synthesis
- Bone health and treatments
- Advanced Breast Cancer Therapies
China Electric Equipment Group (China)
2024
China Electric Power Research Institute
2024
Shandong Institute of Metrology
2024
Arvinas (United States)
2015-2023
State Grid Hebei Electric Power Company
2022
State Grid Corporation of China (China)
2021
Nantong University
2020
Electric Power Research Institute
2020
Yale University
1997-2019
Yangzhou University
2015
Significance We describe the development of a small molecule that mediates degradation bromodomain and extra-terminal (BET) proteins its application in treatment castration-resistant prostate cancer (CRPC). Few therapeutic options exist to treat CRPC, especially CRPC tumors expressing constitutively active androgen receptor (AR) splice variants lack ligand-binding domain can effect androgen-independent transactivation target genes. Importantly, we demonstrate targeted BET using...
Abstract Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, E3 ligases successfully exploited to accomplish this been limited few which small-molecule ligands have discovered. ligase MDM2 is bound nutlin class ligands, there are nutlin-based PROTAC. Because a should both knockdown its target protein and upregulate tumor suppressor p53, we examined ability such decrease cancer cell viability. A nutlin-based, BRD4-degrading...
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein facilitate ubiquitination and subsequent degradation of protein. While the field targeted degraders is still relatively young, potential for this modality become differentiated therapeutic reality strong, such both academic pharmaceutical institutions now entering interesting area research. In article, we describe broadly applicable process identifying degrader hits based on...
Ras-induced malignant transformation requires Ras farnesylation, a lipid posttranslational modification catalyzed by farnesyltransferase (FTase). Inhibitors of this enzyme have been shown to block Ras-dependent transformation, but the mechanism which occurs remains largely unknown. We designed FTI-276, peptide mimetic COOH-terminal Cys-Val-Ile-Met K-Ras4B that inhibited potently FTase in vitro (IC50 = 500 pM) and was highly selective for over geranylgeranyltransferase I (GGTase I) 50 nM)....
The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the receptor β (THR-β) in liver, while adverse effects, including cardiac mediated by α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization this addition a cyanoazauracil substituent improved both potency and selectivity led MGL-3196 (53), which 28-fold for over THR-α functional assay. Compound 53 showed outstanding...
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,...
Prenylation of the carboxyl-terminal CAAX (C, cysteine; A, aliphatic acid; and X, any amino acid) Ras is required for its biological activity. We have designed a peptidomimetic, GGTI-287, which 10 times more potent toward inhibiting geranylgeranyltransferase I (GGTase I) in vitro (IC50 = 5 nM) than our previously reported farnesyltransferase inhibitor, FTI-276. In whole cells, methyl ester derivative GGTI-286, was 25-fold 2 μM) corresponding FTI-276, FTI-277, processing geranylgeranylated...
We have recently reported that the geranylgeranyltransferase I inhibitor GGTI-298 arrests human tumor cells at G1phase of cell cycle and increases protein RNA levels cyclin-dependent kinase p21WAF1/CIP1. Here, we show acts transcriptional level to induce p21WAF1/CIP1 in a pancreatic carcinoma line, Panc-1. This upregulation promoter was selective, since inhibited serum responsive element- E2F-mediated transcription. A functional analysis showed GC-rich region located between positions −83...
The antileukemic effect of inhibiting bromodomain and extra-terminal domain-containing (BET-containing) proteins (BETPs) such as BRD4 has largely been attributed to transcriptional downregulation cellular anabolic antiapoptotic processes, but its on the bone marrow microenvironment, a sanctuary favoring persistence leukemic stem/progenitor cells, is unexplored. Sustained degradation BETP with small-molecule BET proteolysis-targeting chimera (PROTAC) ARV-825 resulted in marked surface CXCR4...
Cysteine farnesylation of the carboxyl-terminal tetrapeptide CAAX (C = Cys, A Leu, Ile, or Val, X Met Ser) oncogene product Ras is required for its malignant transformation activity. As a consequence farnesyltransferase (FTase), enzyme responsible this lipid modification, has become one most sought-after targets anticancer drug development. We have recently designed peptide mimics COOH-terminal Cys-Val-Ile-Met KB-Ras where dipeptide Val-Ile was replaced by aminobenzoic acid derivatives....
We have used specific inhibitors for farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) I as well combinations of lovastatin with geranylgeraniol (GGOH) or farnesol (FOH) to investigate the role protein prenylation in platelet-derived growth factor (PDGF)-induced PDGF receptor tyrosine phosphorylation. NIH-3T3 cells treated highly FTase inhibitor FTI-277 had no effect on phosphorylation activation mitogen-activated kinase (MAPK) at doses that completely inhibit...