The ubiquitin-proteasome system has recently been recognized to play a central role in tumor biology. Bortezomib, an inhibitor of the chymotrypsin-like activity of the proteasome, has clinical activity in a variety of hematologic malignancies and is FDA approved for use in Multiple Myeloma and Mantle Cell Lymphoma.

The present invention for the first time describes that Eeyarestatins, a new class of small molecules, are potential anti-cancer agents. The compounds inhibit the deubiquitination of proteins by targeting the deubiquitination enzymes in the protein degradation pathway. More specifically, the inventors have demonstrated that the Eeyarestatins successfully kill different leukemia and lymphoma cell lines as well as leukemia cells isolated from patients with chronic lymphocytic leukemia by inducing the expression of Noxa, a pro-apoptotic member of the Bcl-2 protein family. Additionally, Eeyarestatins are active against cells that are resistant to Bortezomib and thus can be effective against drug-resistant tumors.