Browsing by title
Now showing items 1291-1310 of 4607
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Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
(NATURE PORTFOLIO, 2022-11-03)By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. ... -
Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70.
(MDPI, 2022-01-26)Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like ... -
Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis.
(AMER CHEMICAL SOC, 2016-10-13)Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth ... -
Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes.
(AMER CHEMICAL SOC, 2023-02-23)The existence of multiple centrosomes in some cancer cells can lead to cell death through the formation of multipolar mitotic spindles and consequent aberrant cell division. Many cancer cells rely on HSET (KIFC1) to cluster ... -
Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.
(ROYAL SOC CHEMISTRY, 2016-08-01)Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents ... -
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
(AMER CHEMICAL SOC, 2017-01-12)Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug ... -
Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A.
(AMER CHEMICAL SOC, 2014-03-27)Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that ... -
Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.
(AMER CHEMICAL SOC, 2023-04-27)B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the ... -
Discovery of high-confidence human protein-coding genes and exons by whole-genome PhyloCSF helps elucidate 118 GWAS loci.
(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2019-12-01)The most widely appreciated role of DNA is to encode protein, yet the exact portion of the human genome that is translated remains to be ascertained. We previously developed PhyloCSF, a widely used tool to identify ... -
Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.
(NATURE PORTFOLIO, 2017-11-30)Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, ... -
Discovery of NEK9 and Aurora A PROTACs using a proteomics-based screening approach
(Institute of Cancer Research (University Of London), 2022-12-12)Chemically induced degradation has emerged as a valuable tool in chemical biology and medicinal chemistry for both potential therapies, and to investigate protein function. Proteolysis targeting chimeras (PROTACs) are small ... -
Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.
(AMER CHEMICAL SOC, 2015-02-26)WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted ... -
Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
(AMER CHEMICAL SOC, 2016-02-11)The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 ... -
Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.
(AMER CHEMICAL SOC, 2018-09-13)Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant ... -
Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.
(AMER ASSOC CANCER RESEARCH, 2018-09-01)Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant ... -
A discrete ordinates Boltzmann solver for application to inverse planning of photons and protons.
(IOP Publishing, 2023-08-29)The aim of this work is to develop a discrete ordinates Boltzmann solver that can be used for calculation of absorbed dose from both photons and protons within an inverse planning optimizer, so as to perform accurate dose ... -
Discriminative identification of transcriptional responses of promoters and enhancers after stimulus
(2017-01-01)Promoters and enhancers regulate the initiation of gene expression and maintenance of expression levels in spatial and temporal manner. Recent findings stemming from the Cap Analysis of Gene Expression (CAGE) demonstrate ... -
Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation.
(eLIFE SCIENCES PUBL LTD, 2022-01-25)BACKGROUND: Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which ...