Small molecule inhibitors of asparagine endopeptidase for the treatment of cancers.
- Nontoxic and specific inhibitors selectively block asparagine endopeptidase (AEP), leaving other related cysteine proteases unaffected.
- Effectively represses the metastasis of breast cancer cells to lungs.
Asparagine endopeptidase (AEP) is implicated in various human disorders including cancers and neurodegenerative diseases. AEP is upregulated in solid tumors and its endoprotease activity has been associated with increased invasive and aggressive behavior of several cancers, including breast, prostate, colorectal and gastric carcinomas. Several inhibitors of AEP have been described; however, they are all peptide-based, subject to proteolytic degradation and tend to exhibit low bioavailability. The current strategy to treat breast cancer is to stratify breast cancer population by markers and have drugs that address the specific sub-populations, but a drug with efficacy against all breast cancer types is favorable.
Emory inventors have identified small-molecule inhibitors of asparagine endopeptidase (AEP). The lead compounds are cell permeable with low cytotoxicity and highly selective for AEP, reducing reactivity to other cysteine proteases. A lead compound was shown to inhibit breast cancer cell migration and invasion without affecting cell viability. In addition, the compound reduces the metastasis of breast cancer cells to lungs in a murine model. This lead compound is a great candidate to treat breast cancer metastasis. Another compound was identified for the treatment of neurological disorders including Alzheimer’s disease.
Lead compounds have been characterized for their pharmacokinetics and toxicity and tested in mouse models.