This Program proposes an overarching hypothesis that rational targeting of ?-secretase, a multi-subunit intramembrane cleaving protease that has several biologically important substrates, may be considered as a therapeutic target for a number of diseases. The three projects in this Program address the use of ?-secretase inhibitors in breast cancer (Project 1), and graft-versus-host disease (Project 2), and propose biochemical strategies to enable us to better understand the mechanism of action of ?-secretase (Project 3). These projects are integrated with a goal of better understanding the mechanism of action of ?-secretase inhibition in normal, as well as, disease settings. The Principal Investigators of this Program have worked together, shared data and published as a group for the past six years. The Program is significantly enhanced by a Chemistry Core that has the proven ability to synthesize a wide variety of ?-secretase inhibitors that allow members of the Program to explore the biological properties of these inhibitors in an environment free from commercial restriction. Such an approach will provide a scientific basis for optimal GSI selection matched to a particular disease.
The development of y-secretase inhibitors targeted for therapy of diseases such as cancer and graft-versus host- disease is likely to significantly impact the treatment of these two important diseases.
|Jung, Joo In; Ran, Yong; Cruz, Pedro E et al. (2014) Complex relationships between substrate sequence and sensitivity to alterations in ?-secretase processivity induced by ?-secretase modulators. Biochemistry 53:1947-57|
|Chinchar, Edmund; Makey, Kristina L; Gibson, John et al. (2014) Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells. Vasc Cell 6:12|
|Dongre, Anushka; Surampudi, Lalitha; Lawlor, Rebecca G et al. (2014) Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4(+) T Cells. Front Immunol 5:54|
|Shin, Hyun Mu; Tilahun, Mulualem E; Cho, Ok Hyun et al. (2014) NOTCH1 Can Initiate NF-?B Activation via Cytosolic Interactions with Components of the T Cell Signalosome. Front Immunol 5:249|
|Zhang, Shubing; Chung, Wen-cheng; Miele, Lucio et al. (2014) Targeting Met and Notch in the Lfng-deficient, Met-amplified triple-negative breast cancer. Cancer Biol Ther 15:633-42|