A5075097409- Protein Degradation and Inhibitors
- Melanoma and MAPK Pathways
- Enzyme Structure and Function
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Cancer Mechanisms and Therapy
- Click Chemistry and Applications
- Protein Kinase Regulation and GTPase Signaling
- Cytokine Signaling Pathways and Interactions
- Multiple Myeloma Research and Treatments
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Metabolism and Genetic Disorders
- Glycosylation and Glycoproteins Research
- Chronic Lymphocytic Leukemia Research
- HIV/AIDS drug development and treatment
- Carbohydrate Chemistry and Synthesis
- Retinoids in leukemia and cellular processes
- Cancer, Hypoxia, and Metabolism
- Protein Structure and Dynamics
- Peroxisome Proliferator-Activated Receptors
- PI3K/AKT/mTOR signaling in cancer
Goethe University Frankfurt
2016-2025
Age UK
2025
Genomics (United Kingdom)
2010-2019
University of Oxford
2010-2019
Genomics England
2011-2018
Structural Genomics Consortium
2017-2018
Science Oxford
2016
Nuffield Health
2016
Oxfam
2014
University of Bristol
2005-2009
Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors the bone morphogenetic protein (BMP) receptor ALK2 (ACVR1) needed urgently to treat progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain only BMP inhibitor chemotype reported date. By screening an assay panel 250...
Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant kinase domains escape regulation leading severely degenerative diseases represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP ALK2 reduce binding inhibitor FKBP12 promote leaky signaling absence ligand. To establish structural...
Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute central scaffolding nucleolar remodeling complex (NoRC) regulates expression noncoding RNAs. However, BAZ2 bromodomains low predicted druggability so far no selective been published. Here we report GSK2801, potent, cell active...
Janus kinases (JAKs) are a family of cytoplasmatic tyrosine that attractive targets for the development anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and inhibitors remains under intensive debate is whether JAK should be isoform selective. Since JAK3 functions restricted to immune cells, an isoform-selective inhibitor could especially valuable achieve clinically more useful precise effects. However, high degree structural conservation makes...
The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery a potent, selective, cell active inhibitor 13 (BAZ2-ICR) bromodomains through rapid optimization weakly potent starting point. A key feature presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies shallow pockets. represents excellent chemical probe for functional studies BAZ2 vitro vivo.
The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing neurological alterations found in individuals with Down syndrome. For an assessment role DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, described literature so far either not sufficiently or have tested against closely related kinases from DYRK and CLK families. aim this study was identification exhibiting selectivity versus structurally functionally...
Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance pro/antiangiogenic normal physiological levels. The lack potency selectivity available compounds has limited development inhibitors, with control by factor-specific kinases yet be translated. We present here that occupy a binding pocket created unique helical insert SRPK1, trigger backbone flip in hinge region, results potent (<10 nM)...
Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET bromodomains, which proven druggable, bromodomains from other regions of the phylogenetic tree shallower pockets. We describe successful targeting challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization high ligand-efficiency fragments into a novel series low-micromolar inhibitors. Our results provide attractive leads for development chemical...
Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using combination of ChIP-seq, ChIP-proteomics, RNA-seq experiments embryonic stem cells where Atad2 is normally highly expressed, we found that an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, repair factors. A structural analysis...
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading discovery BAY-850, potent isoform selective inhibitor that specifically induces bromodomain dimerization prevents interactions with acetylated histones in vitro, as well chromatin cells. These features qualify BAY-850 chemical probe explore biology.
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation these modified lysine-binding has been linked to the onset and progression cancers. We herein report discovery characterisation first small-molecule chemical probe, SGC-iMLLT, for YD MLLT1 (ENL/YEATS1) MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent selective inhibitor MLLT1/3-histone interactions. Excellent selectivity over other human (YEATS2/4) bromodomains was observed....
A DNA-encoded small-molecule library was prepared using yoctoReactor technology followed by binder trap enrichment to identify selective inhibitors with nanomolar potencies against p38α MAP kinase.
Abstract The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I the bromodomain phylogenetic tree. Iterative cycles rational inhibitor design biophysical characterization led to discovery triazolopthalazine‐based L‐45 (dubbed L‐Moses ) as first potent, selective, cell‐active PCAF (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished in enantiopure form. was shown disrupt PCAF‐Brd...
We describe the construction of a DNA-encoded chemical library comprising 148 135 members, generated through self-assembly two sub-libraries, containing 265 and 559 respectively. The was designed to contain building blocks potentially capable forming covalent interactions with target proteins. Selections performed JNK1, kinase conserved cysteine residue close ATP binding site, revealed preferential enrichment 2-phenoxynicotinic acid moiety (building block A82)...
The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in the host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus targeting this domain may offer therapeutic strategy to combat current future virus pandemics. To assist inhibitor development efforts, we report here comprehensive set of crystal structures complexed with diverse naturally occurring nucleotides, small molecules,...
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands redirection of scientific efforts criteria organized research projects. international COVID19-NMR consortium seeks provide such new approaches gathering expertise worldwide. In particular, making available viral proteins RNAs will pave way understanding molecular components in detail. resources provided through are fully disclosed accelerate access exploitation. NMR...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications promote its aggregation the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates cellular animal models; thus, TTBK1 inhibitors emerge as promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase–ligand complex structure determination,...