Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment

Mycophenolic acid (MPA), an inhibitor of IMP-dehydrogenase (IMPDH), is used worldwide in transplantation. Recently, numerous studies showed its importance in cancer treatment. Consequently, MPA entered clinical trials in advanced multiple myeloma patients. Suberoylanilide hydroxamic acid (SAHA), a potent differentiation agent acting through inhibition of histone deacetylases (HDACs), was recently approved for treatment of cutaneous T cell lymphoma. We report herein the synthesis of dual inhibitors of IMPDH and HDACs. We found that mycophenolic hydroxamic acid (9, MAHA) inhibits both IMPDH (K₁ = 30 nM) and HDAC (IC₅₀ = 5.0 μM). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (K_i = 1.7 μM) and HDAC (IC₅₀ = 0.06 μM). Both MAHA (IC₅₀ = 4.8 μM) and SAHA analogue 14 (IC₅₀ = 7.7 μM) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.