Recent development of IMP dehydrogenase inhibitors for the treatment of cancer

Abstract

Inosine 5'-monophosphate dehydrogenase (IMPDH) represents an attractive target for the development of anticancer agents; however, there are no drugs aimed at this target for the treatment of cancer currently available on the market. Tiazofurin, a potent IMPDH inhibitor, reached clinical trials with Orphan Drug status for the treatment of patients in blast crisis of chronic myelogenous leukemia (CML); however, it was considered too toxic for application against other malignancies and no development has been reported for this drug since 2002. Formulations of mycophenolic acid, another potent inhibitor of IMPDH, are currently used for the prevention of rejection following transplantation, and against autoimmune diseases. More recently, numerous studies have demonstrated the potential of mycophenolic acid as an anticancer agent, with a phase I clinical trial in patients with advanced multiple myeloma ongoing. Furthermore, synergy between imantinib and mycophenolic acid in CML treatments has also been reported. Related compounds such as mycophenolic adenine dinucleotides, along with second-generation analogs, are undergoing preclinical evaluation, while another inhibitor of IMPDH, AVN-944, is currently in phase I clinical trials to investigate the treatment of hematological malignancies. This article reviews recent applications of IMPDH inhibitors as anticancer agents, and highlights the progress that has been made in this field.