A5031762628- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Cellular transport and secretion
- RNA regulation and disease
- Click Chemistry and Applications
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Retinal Development and Disorders
- Melanoma and MAPK Pathways
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Cellular Mechanics and Interactions
- Nitric Oxide and Endothelin Effects
- Catalytic C–H Functionalization Methods
- Pharmacological Receptor Mechanisms and Effects
- Cancer-related gene regulation
- Biochemical and Molecular Research
- Mitochondrial Function and Pathology
- Lung Cancer Research Studies
- Asymmetric Hydrogenation and Catalysis
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- RNA modifications and cancer
- Redox biology and oxidative stress
Boundless Bio (United States)
2020-2024
Sierra Wireless (Canada)
2018-2024
Discovery Institute
2015-2023
Sanford Burnham Prebys Medical Discovery Institute
2011-2023
High Throughput Biology (United States)
2023
Sierra Engineering (United States)
2020
Scripps Research Institute
1994-2008
Kalyra Pharmaceuticals (United States)
2003-2007
Howard Hughes Medical Institute
1996-2003
University of California, Berkeley
2003
Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest the cell cycle. A trapoxin affinity matrix was used isolate two nuclear proteins copurified with deacetylase activity. Both were identified by peptide microsequencing, complementary DNA encoding catalytic subunit (HD1) cloned from human Jurkat T library. As predicted protein very similar yeast transcriptional regulator Rpd3p, these results support role for as...
Gene expression is in part controlled by chromatin remodeling factors and the acetylation state of nucleosomal histones. The latter process regulated histone acetyltransferases deacetylases (HDACs). Previously, three human five yeast HDAC enzymes had been identified. These can be categorized into two classes: first class represented Rpd3-like proteins second Hda1-like proteins. Human HDAC1, HDAC2, HDAC3 are members class, whereas no II amino acid sequence Hda1p was used to search...
Treatment of mammalian cells with small molecule histone deacetylase (HDAC) inhibitors induces changes in the transcription specific genes. These correlate directly an increase acetylation levels all four core histones vivo . Antibodies directed against endogenous HDAC1, HDAC2, or HDAC3 immunoprecipitate activity that is inhibited vitro by trapoxin (TPX), and three HDACs are retained a TPX-affinity matrix. HDAC1 HDAC2 associated HeLa complex predominantly separate from immune complex. Both...
Depudecin is a fungal metabolite that reverts the rounded phenotype of NIH 3T3 fibroblasts transformed with v- ras and src oncogenes to flattened nontransformed parental cells. The mechanism detransformation induced by this agent had not been determined. Here, we demonstrate depudecin inhibits histone deacetylase (HDAC) activity effectively both in vivo vitro . induces similar morphological reversion cells as do other naturally occurring HDAC inhibitors such trichostatin A or trapoxin. It...
Abstract Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival 1–7 . At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription–replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses reveal pervasive RNA associated single-stranded DNA,...
ARTEMIS is a member of the metallo-β-lactamase protein family. has endonuclease activity at DNA hairpins and 5'- 3'-DNA overhangs duplex DNA, this endonucleolytic dependent upon DNA-PKcs. There been uncertainty about whether also 5'-exonuclease on single-stranded 5'-overhangs, because not Here, we show that activities co-purify. Second, point mutant putative active site residue (H115A) markedly reduces both activity. Third, divalent cation effects parallel one another. Fourth, can be blocked...
There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, neuropathic pain states. The majority existing inhibitors either based on the structure or substrate competitive. We describe identification from an ultra high-throughput screen a novel series quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies screening hit, coupled with...
Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described identification a series amide-quinolinone dimerization inhibitors although potent, suffered high clearance limited exposure in vivo. By conformationally restricting amide this progenitor series, describe novel...
Abstract Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone inhibitor series was identified that optimized to the lead compound, KD5170. KD5170 inhibited proliferation of myeloma cell lines and viability CD138+ primary cells by induction apoptosis, accompanied increase acetylation histones activation caspase-3, caspase-8, caspase-9. Treatment with caused loss mitochondrial...
Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate effectiveness of existing cancer therapies and overcome resistance drugs such as BRAF inhibitors (BRAFi). Here, we identified characterized small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 disrupts eIF4F complex. SBI-756 impaired assembly independently mTOR attenuated growth BRAF-resistant BRAF-independent melanomas. also suppressed AKT...
Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment cutaneous T-cell lymphoma. Like vorinostat, most small-molecule HDAC in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate catalytic Zn2+ active site HDACs. We sought identify novel, nonhydroxamate-based potentially...
In Caenorhabditis elegans , an X chromosome-counting mechanism specifies sexual fate. Specific genes termed X-signal elements, which are present on the chromosome, act in a concerted dose-dependent fashion to regulate levels of developmental switch gene xol-1 . turn, determine fate and activation state dosage compensation mechanism. The crystal structure XOL-1 protein at 1.55 Å resolution unexpectedly reveals that encodes GHMP kinase family member, despite sequence identity 10% or less....
Abstract Extrachromosomal DNA (ecDNA) presents a major challenge for precision medicine, contributing to poor survival patients with oncogene-amplified tumours. EcDNA renders tumours resistant targeted treatments by facilitating massive transcription of oncogenes and rapid genome evolution. At present, there are no ecDNA- specific treatments. Here we show that enhancing replication conflict enables elimination ecDNA-containing cancers, exposing an actionable vulnerability. Stepwise analyses...
<h2>Summary</h2> High-grade serous ovarian cancers (HGSOCs) with homologous recombination deficiency (HRD) are initially responsive to poly (ADP-ribose) polymerase inhibitors (PARPi), but resistance ultimately emerges. HGSOC <i>CCNE1</i> amplification (<i>CCNE1</i><sup>amp</sup>) associated PARPi and platinum treatments. High replication stress in HRD <i>CCNE1</i><sup>amp</sup> leads increased reliance on checkpoint kinase 1 (CHK1), a key regulator of cell cycle progression the response....
Antiapoptotic Bcl-2 family proteins are validated cancer targets composed of six related proteins. From a drug discovery perspective, these challenging that exert their cellular functions through protein-protein interactions (PPIs). Although several isoform-selective inhibitors have been developed using structure-based design or high-throughput screening (HTS) synthetic chemical libraries, no large-scale screen natural product collections has reported. A competitive displacement fluorescence...
Effective therapy for malignant melanoma, the leading cause of death from skin cancer, remains an area significant unmet need in oncology. The elevated expression PKCε advanced metastatic melanoma results increased phosphorylation transcription factor ATF2 on threonine 52, which causes its nuclear localization and confers oncogenic activities. nuclear-to-mitochondrial translocation following genotoxic stress promotes apoptosis, a function that is largely lost cells, due to confined...