A5049907764- Protein Kinase Regulation and GTPase Signaling
- ATP Synthase and ATPases Research
- Click Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- Receptor Mechanisms and Signaling
- Protein Tyrosine Phosphatases
- Computational Drug Discovery Methods
- RNA Research and Splicing
- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Endoplasmic Reticulum Stress and Disease
- Cellular Mechanics and Interactions
- Heat shock proteins research
- Metal complexes synthesis and properties
- Lymphoma Diagnosis and Treatment
- Melanoma and MAPK Pathways
- Biochemical and Molecular Research
- Microtubule and mitosis dynamics
- Cell Adhesion Molecules Research
- Galectins and Cancer Biology
- bioluminescence and chemiluminescence research
- RNA regulation and disease
- Cancer, Hypoxia, and Metabolism
- Pancreatic function and diabetes
- Retinal Imaging and Analysis
Mucolipidosis IV Foundation
2025
Vanderbilt University
2017-2019
Institute of Cancer Research
2013-2014
St. Jude Children's Research Hospital
2012-2014
Cancer Research UK
2013
Garvan Institute of Medical Research
2008
St Vincent's Hospital Sydney
2008
University of Verona
2003
New York University
2002-2003
University of Turin
2003
OBJECTIVE—Cytokines contribute to β-cell destruction in type 1 diabetes. Endoplasmic reticulum (ER) stress–mediated apoptosis has been proposed as a mechanism for death. We tested whether ER stress was necessary cytokine-induced death and also gene activation present β-cells of the NOD mouse model RESEARCH DESIGN AND METHODS—INS-1 or rat islets were treated with chemical chaperone phenyl butyric acid (PBA) exposed not interleukin (IL)-1β γ-interferon (IFN-γ). Small interfering RNA (siRNA)...
The treatment of tumors driven by overexpression or amplification MYC oncogenes remains a significant challenge in drug discovery. Here, we present new strategy toward the inhibition via disruption protein–protein interaction between and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking association these proteins is hypothesized to disrupt localization chromatin, thus disrupting ability sustain tumorigenesis. Utilizing high-throughput screening campaign subsequent...
Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the GDP for GTP on RAS. In its active form, GTP-bound RAS responsible numerous critical cellular processes. Aberrant activity involved in ∼30% all human cancers; hence, SOS1 an attractive therapeutic target role modulating activation. Here, we describe new series benzimidazole-derived agonists. Using structure-guided design, discovered small molecules increase vitro at submicromolar concentrations,...
Small-molecule lead optimisation in early-stage drug discovery is broadly supported by computational chemistry approaches throughout industry. Over the last decade, Free Energy Perturbation (FEP) has grown into a mature physics-based tool that prospectively guides medicinal decision-making accurately predicting ligand potencies at level of precision required for granular nature stage. Machine-learned ligand-protein co-folding models are forefront accurate protein structure prediction and...
Small-molecule lead optimisation in early-stage drug discovery is broadly supported by computational chemistry approaches throughout industry. Over the last decade, Free Energy Perturbation (FEP) has grown into a mature physics-based tool that prospectively guides medicinal decision-making accurately predicting ligand potencies at level of precision required for granular nature stage. Machine-learned ligand-protein co-folding models are forefront accurate protein structure prediction and...
Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach modulating activity to target and affect proteins that interact with RAS, such as guanine nucleotide exchange factor (GEF) son sevenless homologue 1 (SOS1). Here, we report on structure–activity relationships (SAR) an indole series compounds. Using structure-based...
Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% all human tumors. Therefore, pharmacologic modulation has attracted great interest as a therapeutic strategy. Our laboratory recently discovered small molecules that activate Son Sevenless (SOS)-catalyzed nucleotide exchange on inhibit downstream signaling. Here, we describe how pharmacologically targeting SOS1 induced biphasic RAS-GTP ERK phosphorylation levels, which observed variety cell...
Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over last 30 years, proteins have proven to be recalcitrant therapeutic targets. One approach for modulating is target that interact with RAS, such as guanine nucleotide exchange factor (GEF) son sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds bind SOS1 and activate RAS. Using...
Sil1 is a nucleotide exchange factor for the endoplasmic reticulum chaperone BiP, and mutations in this gene lead to Marinesco-Sjögren syndrome (MSS), debilitating autosomal recessive disease characterized by multisystem defects. A mouse model MSS was previously produced disrupting using gene-trap methodology. The resulting Sil1Gt phenocopies several pathologies associated with MSS, although its ability assemble secrete antibodies, best-characterized substrate of has not been investigated....
Activating mutations in RAS can lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting may perturb multiple signaling pathways simultaneously. One method for modulating is target activity of guanine nucleotide exchange factor SOS1. Our laboratory has discovered compounds that bind SOS1 activate RAS. Interestingly, these agonist elicit biphasic modulation ERK phosphorylation simultaneous inhibition AKT levels....
Abstract The molecular chaperone heat shock protein 90 (HSP90) maintains the conformation, stability and function of oncogenic client proteins, many which are mutated or overexpressed. Therefore, HSP90 is an important cancer therapeutic target. To further increase efficacy inhibitors, combinatorial strategies may be beneficial. Here we report unbiased global screening approach to identify genes that encode potentially druggable proteins modulate cellular responses inhibition. From 7,593 were...
Abstract Heat shock protein 90 (HSP90) is an important cancer therapeutic target. HSP90 chaperone activity maintains the conformation, stability and function of mutated variants over-expressed oncogenic client proteins responsible for driving proliferation human cancer. To further increase efficacy specificity inhibitor treatment, cell response to inhibition can be modulated through use combinatorial therapeutics. An siRNA screen targeting 7,593 genes encoding considered druggable was used...
<p>Treatment with 1 does not cause total protein levels of SPRY2, SPRY4, DUSP4 and DUSP16 to increase. HeLa cells were treated 50 μM over a time course up 180 minutes. EGF (50 ng/mL for 5 minutes) was used as positive control. HCT 116 lysate included control levels. Two biological repeats this experiment independently conducted.</p>
<p>Treatment with 17-AAG does not cause modulation of RAS-GTP levels. HeLa cells were treated 1 μM over a time course up to 180 minutes. EGF (50 ng/mL for 5 minutes) was used as positive control. Two biological repeats this experiment independently conducted.</p>
<p>Modulation of phospho ERK levels is observed at various treatment concentrations 1. HeLa cells were treated with between 6.25 μM to 100 1 for a time course up 30 minutes. Two biological repeats this experiment independently conducted.</p>
<p>Uncropped versions of all western blot membranes</p>
<p>SPRY2 is not phosphorylated on tyrosine residues in response to 1 treatment. 293 cells were transiently transfected with V5-SPRY2 and treated 25 μM over a timecourse of up 90 minutes. Where indicated, FBS (20% v/v) for 15 Two biological repeats this experiment independently conducted.</p>
<p>SPRY2 is not phosphorylated on tyrosine residues in response to 1 treatment cells co-expressing V5-SPRY2 and HA-SOS1 S1178A. 293 were transiently transfected with both S1178A treated 25 μM over a timecourse of up 90 minutes. Where indicated, FBS (20% v/v) for 15 Two biological repeats this experiment independently conducted.</p>