A5043472878- Monoclonal and Polyclonal Antibodies Research
- PI3K/AKT/mTOR signaling in cancer
- Biochemical and Molecular Research
- Cancer, Hypoxia, and Metabolism
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Cytokine Signaling Pathways and Interactions
- SARS-CoV-2 and COVID-19 Research
- Immune Cell Function and Interaction
- Chronic Lymphocytic Leukemia Research
- Cancer Mechanisms and Therapy
- HER2/EGFR in Cancer Research
- Axon Guidance and Neuronal Signaling
- Melanoma and MAPK Pathways
- Lung Cancer Treatments and Mutations
- Electrochemical sensors and biosensors
- Chronic Myeloid Leukemia Treatments
- Glycosylation and Glycoproteins Research
- HIV/AIDS drug development and treatment
- Cancer Genomics and Diagnostics
- Glioma Diagnosis and Treatment
- Cancer therapeutics and mechanisms
- Protein purification and stability
- DNA Repair Mechanisms
- Microtubule and mitosis dynamics
LifeArc
2012-2024
Structural Genomics Consortium
2019-2021
East Sussex Healthcare NHS Trust
2021
McGill University Health Centre
2021
University of Bristol
2020
University of Toronto
2019
Discovery Centre
2017
Intuit (United States)
2017
Stevenage Bioscience Catalyst
2016
Medicines for Malaria Venture
2011-2016
We have generated mice with a deficiency in T1/ST2 expression to clarify the roles of T helper cell type 2 (Th2) responses. Using immunological challenges normally characterized by Th2-like response, we compared responses T1/ST2-deficient those wild-type mice. primary pulmonary granuloma model, induced Schistosoma mansoni eggs, demonstrate that formation, eosinophil infiltration, is abrogated Furthermore, clearly absence expression, levels Th2 cytokine production are severely impaired after...
Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by development resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure PfDHODH was used inform medicinal chemistry allowing identification potent and selective inhibitor (DSM265) that acts...
Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, clinical efficacy which have been compromised by resistance arising through mutations at various sites on enzyme. Here, we describe use cocrystal structures with inhibitors substrates, along pharmacokinetic profiling for design, characterization, preclinical development a selective, highly efficacious, orally available drug candidate that potently inhibits both...
A method is described here for identifying good protease substrates among approximately 10(7) possible sequences. library of fusion proteins was constructed containing an amino-terminal domain used to bind affinity support, followed by a randomized substrate sequence and the carboxyl-terminal M13 gene III. Each protein displayed as single copy on filamentous phagemid particles (substrate phage). Phage were then bound support treated with interest. released, whereas phage that resisted...
Malaria is one of the leading causes severe infectious disease worldwide; yet, our ability to maintain effective therapy combat illness continually challenged by emergence drug resistance. We previously reported identification a new class triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, discovery lead series and novel target for development. Active compounds from contained triazolopyrimidine ring attached an aromatic...
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment malaria in particular, are high priority; however, there few chemically validated targets. The natural product cladosporin is active against blood- liver-stage Plasmodium falciparum Cryptosporidium parvum cell-culture studies. Target deconvolution P. has shown that inhibits lysyl-tRNA synthetase ( Pf KRS1). Here, we report identification a series...
Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role altered glycosylation in resistance antibodies not fully understood. Here, we have generated potent hu5B3.v3 MRCT10.v362 that, similar previously described AP33 HCV1, bind highly conserved linear epitope E2. We utilize combination vitro selections...
Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) an important target for antimalarial chemotherapy. We describe a detailed analysis protein-ligand interactions between DHODH and triazolopyrimidine-based inhibitor series to explore effects fluorine on affinity species selectivity. show that increasing fluorination dramatically increases binding mammalian DHODHs, leading loss...
The precise spatiotemporal control of cell proliferation is key to the morphogenesis epithelial tissues. Epithelial divisions lead tissue crowding and local changes in force distribution, which turn suppress rate divisions. However, molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement B-plexin transmembrane receptors response crowding-induced forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail...
Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection are associated with inappropriate allergic reactions. IL-33–activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that IL-25–activated created an cancer-permissive microenvironment. Colorectal (CRC) patients higher tumor IL25 expression had reduced survival increased IL-25R–expressing tumor-resident...
Leishmania major infection is useful as an experimental model to define factors responsible for the development and maintenance of Th cell immune responses. Studies using inbred mouse strains have identified that Th1 response characteristic C57BL/6 mice results in healing, whereas BALB/c fail control due generation inappropriate Th2 response. We now demonstrate IL-13 a key factor determining susceptibility L. infection. Overexpression transgenic makes normally resistant strain susceptible...
AbstractChk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase response, may be resistance to genotoxic therapies that target synthesis. We studied vitro vivo effects EXEL-9844 (XL844), potent, orally available, specific inhibitor Chk1 Chk2, combination with gemcitabine. clonogenic assays using multiple cell lines vitro, had only minor as single agent but substantially enhanced gemcitabine-induced killing....
Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery ErbB2 mutations that confer small-molecule inhibitor lapatinib.We did in vitro screening using a randomly mutagenized expression library Ba/F3 cells, which were dependent on activity survival and growth.Lapatinib screens identified at 16 different amino acid residues, 12 mutated acids mapping...
ABSTRACT The E2 envelope glycoprotein of hepatitis C virus (HCV) binds to the host entry factor CD81 and is principal target for neutralizing antibodies (NAbs). Most NAbs recognize hypervariable region 1 on E2, which undergoes frequent mutation, thereby allowing evade neutralization. Consequently, there great interest in that conserved epitopes. One such NAb AP33, a mouse monoclonal antibody recognizes conserved, linear epitope potently neutralizes broad range HCV genotypes. In this study,...
Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and thought to promote growth, survival, resistance diverse therapies. Here, we report pharmacologic characterization pyridopyrimidinone derivative XL765 (SAR245409), potent highly selective pan inhibitor class I PI3Ks (α, β, γ, δ) with activity against mTOR. Broad kinase selectivity profiling >130 protein kinases revealed that for mTOR over other kinases. In cellular assays, inhibits...
The substrate specificity of furin, a mammalian enzyme involved in the cleavage many constitutively expressed protein precursors, was studied using phage display. In this method, multitude sequences are displayed as fusion proteins on filamentous particles and ones that cleaved can be purified by affinity chromatography. propagated submitted to additional rounds protease selection further enrich for good substrates. DNA sequencing is used identify sequence. After 6 sorting library comprising...
Abstract Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed various cancers and correlates with tumor growth survival. Resistance to a variety anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors chemotherapeutic agents, has been attributed the absence or attenuation downregulating signals along pathway. Thus, have therapeutic potential as single agents combination other therapies for cancer indications....
Abstract Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 Aβ4-42 are major variants in the Alzheimer brain. has not been considered as a therapeutic target yet. We demonstrate that antibody NT4X its Fab fragment reacting with both free N-terminus of Aβ4-x Aβ3-X mitigated neuron loss Tg4-42 mice expressing completely rescued spatial reference memory deficits after passive immunization. also working wild type induced by intraventricular injection Aβ4-42. reduced Aβ3-x, Aβx-40...
The vast majority of clinically approved protein kinase inhibitors target the ATP-binding pocket directly. Consequently, many have broad selectivity profiles and most significant off-target effects. Allosteric are generally more selective, but difficult to identify because allosteric binding sites often unknown or poorly characterized. Aurora-A is activated through TPX2 an site on catalytic domain, this knowledge could be exploited generate inhibitor. Here, we generated inhibitor based a...
Serpins exhibit a range of physiological roles and can contribute to certain disease states dependent on their various conformations. Understanding the mechanisms large-scale conformational reorganizations serpins may lead better understanding in cardiovascular diseases. We have studied serpin, plasminogen activator inhibitor 1 (PAI-1), both active latent state found that anionic halide ions play role active-to-latent structural transition. Crystallographic analysis stable mutant form PAI-1...