A5045584034- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- CRISPR and Genetic Engineering
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- RNA and protein synthesis mechanisms
- Click Chemistry and Applications
- Synthesis and biological activity
- interferon and immune responses
- RNA Interference and Gene Delivery
- RNA regulation and disease
- Genomics, phytochemicals, and oxidative stress
- Nitrogen and Sulfur Effects on Brassica
- Lipid Membrane Structure and Behavior
- Catalytic Cross-Coupling Reactions
- Computational Drug Discovery Methods
- Energy Harvesting in Wireless Networks
- Melanoma and MAPK Pathways
- CO2 Reduction Techniques and Catalysts
- Reproductive Biology and Fertility
- DNA Repair Mechanisms
- Genetics, Bioinformatics, and Biomedical Research
- Carbon dioxide utilization in catalysis
- Advanced biosensing and bioanalysis techniques
- RNA modifications and cancer
Institute for Research in Biomedicine
2021-2024
CeMM Research Center for Molecular Medicine
2019-2024
Austrian Academy of Sciences
2014-2024
Spanish National Cancer Research Centre
2016-2018
Centro de Investigación del Cáncer
2017
Highlights•A stem cell line improves CRISPR-mediated deletions in primary mammalian cells•CDC25A deficiency renders cells resistant to ATR inhibitors•ATR inhibition generates replication stress and promotes premature mitotic entry•The toxicity of inhibitors is due DSBs generated mitosisSummaryOne recurring theme drug development exploit synthetic lethal properties as means preferentially damage the DNA cancer cells. We others have previously developed kinase, shown be particularly genotoxic...
Abstract Molecular glue degraders are an effective therapeutic modality, but their design principles not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin the DDB1–CUL4–RBX1 E3 ligase. Here, investigate how chemically dissimilar small molecules trigger degradation, we evaluated 91 candidate in structural, biophysical and cellular studies reveal all acquire activity via simultaneous CDK12 binding engagement of DDB1...
Metabolic alterations in cancer precipitate associated dependencies that can be therapeutically exploited. To meet this goal, natural product-inspired small molecules provide a resource of invaluable chemotypes. Here, we identify orpinolide, synthetic withanolide analog with pronounced antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR-Cas9 screens, orpinolide disrupts Golgi homeostasis mechanism requires active...
The recent development of haploid cell lines has facilitated forward genetic screenings in mammalian cells. These include near-haploid human isolated from a patient with chronic myelogenous leukemia (KBM7 and HAP1), as well embryonic stem cells derived several organisms. In all cases, haploidy was shown to be an unstable state, so that cultures rapidly become enriched diploids. Here we show the observed diploidization is due proliferative disadvantage compared diploid Accordingly,...
p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of signaling has been linked several diseases including inflammation, immune disorders cancer, suggesting targeting could be therapeutically beneficial. Over last two decades, inhibitors have developed, which showed promising effects pre-clinical studies but results from clinical trials disappointing, fueling interest generation alternative...
MEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency embryonic stem cells (ESCs). However, mechanisms by which condition limits ESC differentiation and whether RAS proteins are involved this phenomenon remain poorly understood. Here we show that nullyzygosity reduces growth of mouse ESCs (mESCs) prohibits their differentiation. Upon deficiency or inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor),...
Lithium-Ion BatteriesIn their Communication (e202315628), De-en Jiang et al. reveal through machine-learning force field molecular dynamics simulations the superionic Li + transport in glassy LiTaCl 6 via adynamic "monkey bar" mechanism.
ABSTRACT Recent drug discovery breakthroughs led to the approval of KRAS G12C inhibitors in lung adenocarcinoma (LUAD). Unfortunately, clinical responses remain limited due rapid resistance onset. Proteolysis-targeting chimeras (PROTACs) have emerged as promising alternatives traditional inhibition. However, there is mechanistic understanding degradation vivo . Here, we developed a preclinical LUAD mouse model and demonstrated that targeted oncogenic induces tumor regression....
Multiomics-driven elucidation of RBS-10 as a prodrug bioactivated by the enzyme NQO1 is reported Antoni Riera, Cristina Mayor-Ruiz et al. in their Research Article (e202316730). shows preferential cytotoxicity against cancer cells pan-resistant to degraders.
The most important quality of arole model is their ability to inspire and positively influence others through actions, integrity,a nd empathy… My motto is:' journey athousand miles begins with as ingle step.' " Find out more about Xiaoyu Tang in his Introducing… Profile.
Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on hijacked proteolysis machinery, which can also as an entry point for resistance. To fully harness potential of targeted protein degradation, it is crucial comprehend resistance mechanisms formulate effective strategies overcome them. We conducted a chemical screening identify synthetic lethal vulnerabilities...
Abstract Metabolic alterations in cancer precipitate associated dependencies that can be therapeutically exploited. To meet this goal, natural product inspired small molecules provide a resource of invaluable chemotypes. Here, we identify orpinolide, synthetic withanolide analog with pronounced anti-leukemic properties via orthogonal chemical screening. Through multi-omics profiling and genome-scale CRISPR/Cas9 screens, orpinolide disrupts Golgi homeostasis mechanism requires active...