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

Liqiang Chen, Daniel Wilson, Hiremagalur N. Jayaram, Krzysztof W. Pankiewicz

50 Scopus citations

Abstract

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 (Ki = 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.

Original languageEnglish (US)
Pages (from-to)6685-6691
Number of pages7
JournalJournal of Medicinal Chemistry
Volume50
Issue number26
DOIs
StatePublished - Dec 27 2007

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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