Approximately 20-30% of breast cancer patients have tumors that over-express human epidermal growth factor receptor (HER2), which confers an aggressive tumor phenotype and poor prognosis. ADAM proteases are responsible for amplification of HER2 signaling due to either cleavage of its extracellular domain or release of HER2 ligands, which leads to proliferation and inhibition of apoptosis. ADAM proteases implicated in amplification of HER2 signaling are ADAM10 and 17;therefore, inhibition of these proteases represents a viable approach to the abrogation of HER2 signaling in breast cancer.
The specific aims of this proposal, therefore, will focus on (1) screening of the MLPCN library for inhibitors that interact with exposits of ADAM10 and 17, and (2) medicinal chemistry optimization of initial leads in order to develop molecular probes of ADAM10 and 17. Our laboratory is uniquely positioned to achieve these goals due to expertise in development of exposited-binding inhibitors and probes, HTS, and biochemistry of proteases. We will also collaborate with experts in the fields of peptide synthesis, HTS, and medicinal chemistry. The successful completion of the Aims of this proposal will lead to a discovery of novel, potent, and selective small molecule probes for ADAM10 and 17. Using these selective molecular probes alone or in combination with other tools, such as siRNA, antibodies, and other small molecule inhibitors, the researchers will be able to study contributions not only of individual members of the ADAM protease family, but also the interplay of ADAM protease-controlled pathways with other pathways implicated in the progression of breast cancer.
Breast cancer is characterized by uncontrolled growth and metastasis of cancer cells. The present research proposes to discover inhibitors for enzymes that participate in control of cell proliferation. These inhibitors could be used as potential drug leads for developing novel anti-cancer therapeutics.
|Madoux, Franck; Dreymuller, Daniela; Pettiloud, Jean-Phillipe et al. (2016) Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate. Sci Rep 6:11|
|Knapinska, Anna M; Dreymuller, Daniela; Ludwig, Andreas et al. (2015) SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of A Disintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes. J Med Chem 58:5808-24|
|Rodriguez, Maria C; Yegorova, Svetlana; Pitteloud, Jean-Philippe et al. (2015) Thermodynamic Switch in Binding of Adhesion/Growth Regulatory Human Galectin-3 to Tumor-Associated TF Antigen (CD176) and MUC1 Glycopeptides. Biochemistry 54:4462-74|
|Wang, Hongjie; Nefzi, Adel; Fields, Gregg B et al. (2014) AlphaLISA-based high-throughput screening assay to measure levels of soluble amyloid precursor protein ?. Anal Biochem 459:24-30|
|Onwuha-Ekpete, Lillian; Tack, Lisa; Knapinska, Anna et al. (2014) Novel pyrrolidine diketopiperazines selectively inhibit melanoma cells via induction of late-onset apoptosis. J Med Chem 57:1599-608|
|Chavaroche, Anais; Cudic, Mare; Giulianotti, Marc et al. (2014) Glycosylation of a disintegrin and metalloprotease 17 affects its activity and inhibition. Anal Biochem 449:68-75|
|Stawikowska, Roma; Cudic, Mare; Giulianotti, Marc et al. (2013) Activity of ADAM17 (a disintegrin and metalloprotease 17) is regulated by its noncatalytic domains and secondary structure of its substrates. J Biol Chem 288:22871-9|
|Minond, Dmitriy; Cudic, Mare; Bionda, Nina et al. (2012) Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates. J Biol Chem 287:36473-87|