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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 | Year: 2010

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.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 155.96K | Year: 2002

DESCRIPTION (provided by applicant): Chemical probes will be developed to profile toxicities resulting from drug interactions. We have developed fluorescent probes that exclusively identify active members of the serine hydrolase super-family of enzymes. Using our technique, we can elucidate activity profiles of diseases, and broadly investigate interactions between the proteome and potential therapeutics. This technology could be used to determine molecular toxicological profiles, rapidly and inexpensively, early in the drug development process. To expand the range of detectable toxicologies, we will design, synthesize, and characterize probes for the following pharmacologically interesting families: kinases, phosphatases, and cytochromes P450. Phase I will demonstrate the use of our current probes in investigating the protein interactions of various inhibitors of enzymes implicated in the etiology of diabetes, obesity, and Alzheimers disease. In phase II we will design and synthesize probes for kinases, phosphatases, cytochromes P450, and cysteine proteases. Phase II will include profiling various compounds and tissue sources, identifying toxicological markers, and creating a database of tissue-specific protein-compound interactions. PROPOSED COMMERCIAL APPLICATIONS: A service for accurately screening potential drugs for toxicity before animal trials will be commercialized. The database component will also be marketed for interrogation with proteomas, targets, or compounds.

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.

Johnson D.S.,Pfizer | Stiff C.,Pfizer | Nomanbhoy T.K.,ActivX Biosciences | Cravatt B.F.,Scripps Research Institute | Ahn K.,Pfizer
ACS Medicinal Chemistry Letters | Year: 2011

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (kinact/Ki and IC50 values of 40300 M-1 s-1 and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials. © 2010 American Chemical Society.

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 | Year: 2011

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.

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