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Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.
(AMER CHEMICAL SOC, 2020-04-23)
Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). ...
Structural and functional characterisation of human RNA helicase DHX8 provides insights into the mechanism of RNA-stimulated ADP release.
(PORTLAND PRESS LTD, 2019-09-13)
DHX8 is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the spliceosome. Here, we report the biochemical characterisation of full-length human DHX8 and the catalytically ...
Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.
(NATURE PORTFOLIO, 2020-04-21)
Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another ...
Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA.
(CELL PRESS, 2020-07-02)
Structural maintenance of chromosomes (SMC) complexes are essential for genome organization from bacteria to humans, but their mechanisms of action remain poorly understood. Here, we characterize human SMC complexes condensin ...
New tricks for an old dog: Brf2-dependent RNA Polymerase III transcription in oxidative stress and cancer.
(TAYLOR & FRANCIS INC, 2018-01-01)
Here, we discuss the role of Brf2, an RNA Polymerase III core transcription factor, as a master switch of the oxidative stress response. We highlight the interplay of Brf2 with the Nrf2/Keap1 pathway, as well as the role ...
RNA polymerase I, bending the rules?
(WILEY, 2017-09-15)
Transcription initiation is one of the key regulatory steps in expressing the genetic information encoded in the DNA. Mechanisms of RNA Pol II transcription have been extensively studied, whereas the structural basis of ...
RavN is a member of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases.
(PUBLIC LIBRARY SCIENCE, 2018-02-01)
The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational ...
High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.
(AMER ASSOC CANCER RESEARCH, 2019-10-01)
BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly ...
Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
(CELL PRESS, 2019-06-26)
Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS ...
C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays.
(ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2019-09-01)
Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit ...