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 (Ki=30 nM) and HDAC (IC50=5.0 microM). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (Ki=1.7 microM) and HDAC (IC50=0.06 microM). Both MAHA (IC50=4.8 microM) and SAHA analogue 14 (IC50=7.7 microM) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.
Center for Drug Design, University of Minnesota, Minneapolis 55455, USA.
Liqiang
L
Chen
Daniel
D
Wilson
Hiremagalur N
HN
Jayaram
Krzysztof W
KW
Pankiewicz
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020014:K562 Cells; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077337:Vorinostat
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D007168:IMP Dehydrogenase; D006655:Histone Deacetylases; D009173:Mycophenolic Acid