ML364

ML364 is a small molecule inhibitor of Ubiquitin Specific Peptidase 2 (USP2), a deubiquitinating enzyme that regulates the stability of various proteins involved in cell cycle progression and metabolism. Identified through the NIH Molecular Libraries Program, ML364 acts as a chemical probe to study the role of USP2 in cancer. By inhibiting USP2, ML364 facilitates the ubiquitination and subsequent proteasomal degradation of substrates such as Cyclin D1 and Skp2. In colorectal cancer models, ML364 has been shown to suppress the Skp2/Akt/HK2 signaling axis and aerobic glycolysis, which helps to overcome resistance to 5-fluorouracil (5-Fu) and sensitize tumor cells to chemotherapy.