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San Diego, CA, United States

Yang Q.,Scripps Research Institute | Deng X.,Dana-Farber Cancer Institute | Lu B.,Scripps Research Institute | Cameron M.,Scripps Research Institute | And 5 more authors.
Cancer Cell

BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1-targeted cancer treatment in animals. © 2010 Elsevier Inc. Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.06M | Year: 2003

DESCRIPTION (provided by applicant): ActivX Biosciences (ActivX) will develop and validate a novel toxicoproteomics platform to correlate changes in protein activity with compound toxicology. This platform uses fluorescent chemical probes to interrogate catalytically active proteins related by super-family derived from any biological sample. Alterations in protein activity are expected to be more interpretable and relevant to toxicant molecular mechanism than the more commonly used transcript-profiling approaches. This Phase II study will demonstrate the utility of this protein activity platform. This study has several stages. 1) The platform will be established as a predictive platform for compound toxicity by investigating protein activities of a) cell lines and b) tissues from animals exposed to compounds that have been well-studied using pharmacology, genomics, and other techniques. 2) The resulting protein activity profiles will be integrated into a database that also includes publicly available transcription data, and will allow for seamless correlation of treatments with changes in protein activity levels of the serine hydrolase, cysteine protease, kinase, epoxide hydrolase, and glutathione-S-transferase families. The activity-based probes (ABPs) for some of these enzyme families are cell-permeable, which is a useful feature that allows for in vivo, rather than in vitro measurements of protein activity in cell lines. 3) Cell-permeable derivatives of ABPs that are currently not cell permeable will be synthesized. 4) To expand the breadth of our profiling abilities, ActivX will also design, synthesize and validate ABPs for the phosphatase and cytochrome P450 families. This platform will be useful for detecting toxicity of chemicals, including therapeutics, and will be important for classifying and exploring the molecular basis of toxicities. Therefore, this technology has a great potential for reducing the time and cost in early compound development, and for revealing underlying toxicity mechanisms of different compounds. ActivX plans to commercialize its technology by establishing a toxicoproteomic database, and by providing a service to the pharmaceutical industry that will detect toxicities of compounds early in the drug screening process.

Choi H.G.,Dana-Farber Cancer Institute | Choi H.G.,Harvard University | Zhang J.,University of Dundee | Deng X.,Dana-Farber Cancer Institute | And 9 more authors.
ACS Medicinal Chemistry Letters

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5- chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 μM in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg. © 2012 American Chemical Society. Source

Deng X.,Dana-Farber Cancer Institute | Deng X.,Harvard University | Dzamko N.,University of Dundee | Prescott A.,University of Dundee | And 10 more authors.
Nature Chemical Biology

Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease. © 2011 Nature America, Inc. All rights reserved. Source

Villamor J.G.,Max Planck Institute for Plant Breeding Research | Kaschani F.,Max Planck Institute for Plant Breeding Research | Kaschani F.,University of Duisburg - Essen | Colby T.,Max Planck Institute for Plant Breeding Research | And 5 more authors.
Molecular and Cellular Proteomics

Many protein activities are driven by ATP binding and hydrolysis. Here, we explore the ATP binding proteome of the model plant Arabidopsis thaliana using acyl-ATP (AcATP)1 probes. These probes target ATP binding sites and covalently label lysine residues in the ATP binding pocket. Gel-based profiling using biotinylated AcATP showed that labeling is dependent on pH and divalent ions and can be competed by nucleotides. The vast majority of these AcATP-labeled proteins are known ATP binding proteins. Our search for labeled peptides upon in-gel digest led to the discovery that the biotin moiety of the labeled peptides is oxidized. The in-gel analysis displayed kinase domains of two receptor-like kinases (RLKs) at a lower than expected molecular weight, indicating that these RLKs lost the extracellular domain, possibly as a result of receptor shedding. Analysis of modified peptides using a gel-free platform identified 242 different labeling sites for AcATP in the Arabidopsis proteome. Examination of each individual labeling site revealed a preference of labeling in ATP binding pockets for a broad diversity of ATP binding proteins. Of these, 24 labeled peptides were from a diverse range of protein kinases, including RLKs, mitogen-activated protein kinases, and calcium-dependent kinases. A significant portion of the labeling sites could not be assigned to known nucleotide binding sites. However, the fact that labeling could be competed with ATP indicates that these labeling sites might represent previously uncharacterized nucleotide binding sites. A plot of spectral counts against expression levels illustrates the high specificity of AcATP probes for protein kinases and known ATP binding proteins. This work introduces profiling of ATP binding activities of a large diversity of proteins in plant proteomes. The data have been deposited in ProteomeXchange with the identifier PXD000188. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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