A5088744518- Chronic Lymphocytic Leukemia Research
- CRISPR and Genetic Engineering
- PI3K/AKT/mTOR signaling in cancer
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- Melanoma and MAPK Pathways
- Muscle Physiology and Disorders
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Viral Infectious Diseases and Gene Expression in Insects
- Enzyme Structure and Function
- Skin and Cellular Biology Research
- Hair Growth and Disorders
- DNA and Nucleic Acid Chemistry
- HER2/EGFR in Cancer Research
- Animal Genetics and Reproduction
- Peptidase Inhibition and Analysis
- Pluripotent Stem Cells Research
- Neurogenetic and Muscular Disorders Research
- Chronic Myeloid Leukemia Treatments
- Protease and Inhibitor Mechanisms
- Chromosomal and Genetic Variations
- Protein Degradation and Inhibitors
- Neuropeptides and Animal Physiology
- Bipolar Disorder and Treatment
Merck (United Kingdom)
2013
Oulu University Hospital
2013
University of Oulu
2013
Ingenium (Germany)
2001-2011
Phenex Pharmaceuticals (Germany)
2003-2011
Menlo Systems (Germany)
2010
Max Planck Society
2005
Max Planck Institute of Biochemistry
2001-2004
The Honourable Society of Lincoln's Inn
2003
National Hospital for Neurology and Neurosurgery
2003
Degenerative disorders of motor neurons include a range progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal (SMA). Although the causative genetic alterations are known for some cases, molecular basis many SMA SBMA-like syndromes most ALS cases is unknown. Here we show that missense point mutations in cytoplasmic dynein heavy chain result neuron degeneration heterozygous mice, homozygotes this accompanied by formation...
Abstract The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a ‘copy and paste’ mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p) 1 . ORF2p reverse transcriptase (RT) endonuclease activities have been implicated in pathophysiology cancer 2,3 , autoimmunity 4,5 ageing 6,7 making potential therapeutic target. However, lack structural mechanistic knowledge hampered efforts to...
Despite the development of a number efficacious kinase inhibitors, strategies for rational design these compounds have been limited by target promiscuity. In an effort to better understand nature inhibition across kinome, especially as it relates off-target effects, we screened well-defined collection inhibitors using biochemical assays inhibitory activity against 234 active human kinases and complexes, representing all branches kinome tree. For our study employed 158 small molecules...
Dipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl (preferentially postproline) associated with pathophysiological roles in immune response cancer biology. While the DPP family member DPP4 is extensively characterized molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures ligand-/substrate-binding modes DPP8 DPP9 have not been reported. In this study we describe crystal human (2.5 Å) (3.0 unliganded complexed noncanonical...
A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures example compounds from this in complex with the catalytic domain PDE1B and PDE10A were determined, allowing optimization potency PDE selectivity. Reduction hERG affinity led to greater than a 3000-fold selectivity for over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one...
Abstract Mutations in a protein designated Parkin were shown to be involved the pathogenesis of autosomal recessive juvenile parkinsonism. Nothing is known about its regional and subcellular distribution mouse. In order elucidate mRNA adult mouse, mouse cDNA was cloned polyclonal antisera generated against N‐terminal part Parkin. The antibodies specific using Western blot analysis, immunostaining cells transfected with pre‐absorption tests. expression profile studied immunohistochemistry...
Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority reported describe reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles then used them discover covalent irreversible inhibitors report successful acrylamide- epoxide-terminated Bruton's Tyrosine Kinase (BTK)...
The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism this benefit is from the depletion pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative to selectively inhibit cell-specific immunoproteasome deplete spare nonhematopoietic cells. Here, we disclose development...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field cancer immunotherapy, upregulation IDO1 in certain cancers been linked host immune evasion and poor prognosis for patients. In particular, inhibition is combination therapy with checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, diamide class compounds was identified promising lead IDO1. While hit 1 possessed attractive cell-based potency, it suffered from...
The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition the interaction between NRF2 and its main negative regulator KEAP1 attractive strategy toward neuroprotective agents. We report here identification nonacidic tetrahydroisoquinolines (THIQs) that inhibit KEAP1/NRF2 protein–protein interaction. Peptide SAR at one residue utilized as a tool to probe structural changes within specific pocket binding site. used information from peptide screening P2...
B-Raf represents an attractive target for anticancer therapy and the development of small molecule inhibitors has delivered new therapies metastatic melanoma patients. We have discovered a novel class molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro vivo. Investigations into structure-activity relationships series are presented along with efforts to improve upon cellular potency, solubility, pharmacokinetic profile. Compounds selectively inhibited showed preferential...
G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods human evolution. Indeed, several genomic loci with signatures recent selection humans contain genes among them X-chromosomally located gene for GPR82. This encodes a so-called orphan unknown function. To address functional relevance GPR82 gene-deficient mice were characterized. GPR82-deficient viable,...