| gamma-Secretase is an aspartyl protease that controls the proteolysis of a multitude of substrates that include the amyloid precursor protein (APP) as well as the Notch proteins. Cleavage of APP generates heterogeneous C-terminal beta-amyloid peptides (Abeta40 and Abeta42) that form the neurotoxic Abeta-species associated with Alzheimer disease (AD). Recent studies suggest that Abeta40 plays a protective role whereas Abeta42 more readily aggregates to form toxic oligomers. gamma-Secretase also cleaves Notch, which regulates cell fate decisions in many physiological processes. Aberrant Notch signaling leads to the development of solid and hematopoietic neoplasms. Due to the central role of gamma-secretase in numerous disorders, much effort has focused on generating gamma-secretase targeted therapeutics. Development of inhibitors that selectively target its individual pathological pathways is necessary for effective therapeutic implementation.;In order to generate selective inhibitors of gamma-secretase, we have developed gamma-secretase assays and screened chemical libraries consisting of approximately 200,000 compounds. Using these assays, we have identified new scaffolds of gamma-secretase inhibitors (GSI). One particular coumarin-dimer based scaffold preferentially abrogates Abeta42 generation over Abeta40 and Notch in vitro and in cell-based systems. We have demonstrated that this novel class of inhibitors modulates gamma-secretase activity by binding to an allosteric site. This interaction causes an alteration of the S1 and S2 catalytic subsites and results in inhibitory selectivity. Our work reports an unprecedented class of GSIs for AD drug development and provides a molecular basis for the design of Abeta42 selective inhibitors.;The role of gamma-secretase in B-cell neoplasms has been controversial. We have determined that Notch plays a tumorigenic role in Non-Hodgkin's lymphoma (NHL) using pharmacological and genetic approaches. Treatment of NHL cells with GSI inhibits cellular proliferation by downregulating Notch signaling and the downstream HES-1 effector. Lastly, ongoing studies are evaluating our GSIs in an animal model of disseminated Burkitt's lymphoma.;These projects present an Abeta42-selective GSI and offer mechanistic evidence to explain how gamma-secretase achieves cleavage specificity. Additionally, we have identified Notch as a tumorigenic factor in Burkitt's lymphoma and establish that it is a viable therapeutic target. Ultimately, these studies will contribute to the development of AD and cancer therapy. |
