Molecular screen for isopeptidase inhibitors to treat pulmonary disease
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AbstractDESCRIPTION (provided by applicant): AMSH is a recently described ubiquitin isopeptidase that is associated with endosomal trafficking of the human epithelial growth factor receptor (EGFR). The ubiquitin pathway is closely involved in the signal transducti on and trafficking mechanisms that regulate the cellular activity of the EGFR. The ubiquitin E3 ligase Cbl promotes the ubiquitination and sorting of the EGFR to late endosomes and lysosomes, where it is degraded by acidic proteases, and the deubiquitinati ng enzyme AMSH abrogates this effect by removing ubiquitin from EGFR, permitting it to recycle to the membrane and retain its ability to regulate cell growth and division. It has been shown that purified AMSH removes ubiquitin from EGFR in vitro, and that siRNA mediated ablation of AMSH in HeLa cells results in increased EGFR degradation (McCullough, Clague et al. 2004). It should thus be possible to discover inhibitors of AMSH that mimic the effects of siRNA in cells. EGFR is a well-established target for cancer drug discovery, either as a receptor or a kinase. It has recently been shown that EGFR is also an attractive target for the discovery of compounds that act against mucus hypersecretion and fibrosis associated with chronic pulmonary disease. It is pr oposed in this one-year Phase I application to develop a novel assay for the deubiquitinase enzyme AMSH and configure it for high throughput screening; this assay will be used in Phase II to discover novel inhibitors that will reduce the cellular level and activity of EGFR and thereby have activity against pulmonary disease by a new mechanism that exploits the physiological regulation of the EGFR, as opposed to attacking it directly. In addition, in Phase I, nonspecific ubiquitin isopeptidase inhibitors wil l be tested in in vitro assays for isopeptidase activity and in cell based assays for attenuation of EGFR. The ultimate commercial goal of the development of an assay for AMSH is to discover a drug with efficacy against asthma, COPD, and other chronic pulm onary diseases. AMSH is a recently described ubiquitin isopeptidase, an enzyme that removes ubiquitin from EGFR, preventing its degradation and permitting it to recycle to the membrane and retain its ability to regulate cell growth and division. It has rec ently been shown that EGFR, already known to be a therapeutic target for neoplastic disease, is also an attractive target for the discovery of compounds that act against mucus hypersecretion and fibrosis associated with chronic pulmonary disease (COPD). Pr ogenra proposes to develop an assay to measure AMSH activity in a high throughput mode so that, in Phase II, compounds can be screened to find inhibitors of AMSH that may have activity in COPD and other pulmonary diseases.
* information listed above is at the time of submission.