A5003527108- Heat shock proteins research
- ATP Synthase and ATPases Research
- Computational Drug Discovery Methods
- thermodynamics and calorimetric analyses
- Enzyme Structure and Function
- DNA Repair Mechanisms
- Toxin Mechanisms and Immunotoxins
- PARP inhibition in cancer therapy
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Quinazolinone synthesis and applications
- Cancer therapeutics and mechanisms
- Mitochondrial Function and Pathology
- Lung Cancer Treatments and Mutations
- Genetic Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
- Effects of Radiation Exposure
- Endoplasmic Reticulum Stress and Disease
- Mass Spectrometry Techniques and Applications
- Protein purification and stability
- Influenza Virus Research Studies
- 14-3-3 protein interactions
- Immune Response and Inflammation
- Analytical Chemistry and Chromatography
- Radiation Therapy and Dosimetry
University of Notre Dame
2017-2021
UCB Pharma (United Kingdom)
2019-2021
University of Kansas
2017-2019
Notre Dame of Dadiangas University
2018
Pearl River Community College
2002
A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors epidermal growth factor receptor (EGFR) and human (HER-2) tyrosine kinases have been prepared. These have, at the C-6 position, butynamide, crotonamide, methacrylamide Michael acceptors bearing water-solublilizing substituents. compounds were prepared by acylation 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show...
A series of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors EGFR and HER-2 kinases have been prepared. These have, at the 6-position, butynamide, crotonamide, methacrylamide Michael acceptors bearing water-solublilizing substituents. compounds were prepared by acylation 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing attaching a...
Abstract Tumour necrosis factor (TNF) is a cytokine belonging to family of trimeric proteins; it has been shown be key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF the target several successful biologic drugs, attempts design small molecule therapies directed this have not led approved products. Here we report discovery potent inhibitors that stabilise an asymmetrical form soluble trimer, compromising signalling inhibiting functions vitro vivo....
Abstract Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising distorted trimer reduce the number of receptors bound to from three two. Here present biochemical structural characterisation molecule-stabilised TNF-TNFR1 complex, providing insights into how can alter signalling function. We demonstrate inhibitors binding affinity third molecule. In support...
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression cancer, and consequently, inhibition Hsp90 folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with N-terminal inhibitors have encountered deleterious side effects toxicities, which appear result from pan-inhibition all four isoforms. Therefore,...
Advanced head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge due to the development of therapy resistance. Several studies have implicated cancer stem cells as possible mechanism for resistance in HNSCC. Heat shock protein 90's (Hsp90's) molecular chaperone function is pathways Therefore, present study, we investigated efficacy novel C-terminal Hsp90 inhibitors (KU711 KU757) targeting HNSCC (CSCs). Treatment human lines MDA1986, UMSCC 22B, 22B cisplatin-resistant...
Abstract PARP inhibitors (PARPi) have become a new line of therapy for Homologous Recombination (HR)-deficient cancers. However, resistance to PARPi has emerged as major clinical problem. DNA polymerase theta (POLθ) is synthetic lethal with HR and druggable target in HR-deficient Here, we identified the antibiotic Novobiocin (NVB) specific POLθ inhibitor that selectively kills tumor cells vitro vivo . NVB directly binds ATPase domain, inhibits its activity, phenocopies depletion....
Novologues KU-32 and KU-596 bind at the C-terminal domain of Hsp90 exploit a long-range allosteric network to modulate chaperone cycle.
Native mass spectrometry is now a well-established method for the investigation of protein complexes, specifically their subunit stoichiometry and ligand binding properties. Recent advances allowing analysis complex mixtures lead to an increasing diversity complexity in spectra obtained. These can be time-consuming tackle through manual assignment challenging automated approaches.
Heat shock protein 90 (Hsp90) is a eukaryotic chaperone responsible for the folding and functional activation of numerous client proteins, many which are oncoproteins. Thus, Hsp90 inhibition has been intensely pursued, resulting in development potential inhibitors, not all well-characterized. inhibitors only abrogate its functions, but also could help us gain insight into structure-function relationship this chaperone. Here, using biochemical cell-based assays along with isothermal titration...
Expansion of the polyglutamine tract in N terminus Ataxin-1 is main cause neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1). However, C-terminal part protein - including its AXH domain and a phosphorylation on residue serine 776 also plays crucial role disease development. This event known to be for interaction with 14-3-3 adaptor proteins has been shown indirectly contribute stability. Here we show that direct anti-aggregation or "chaperone" effect Ataxin-1. Furthermore,...
Two previously identified Hsp90 C-terminal inhibitors were merged into a single scaffold that manifested improved inhibitory activity.
Measurements of protein higher order structure (HOS) provide important information on stability, potency, efficacy, immunogenicity, and biosimilarity biopharmaceuticals, with a significant number techniques methods available to perform these measurements. The comparison the analytical performance HOS standardization results is, however, not trivial task, due lack reference protocols measurement procedures. Here, we developed protocol structurally alter compare samples somatropin, recombinant...
Abstract The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression cancer, and consequently, inhibition Hsp90 folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with N‐terminal inhibitors have encountered deleterious side effects toxicities, which appear result from pan ‐inhibition all four isoforms....