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

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

Research output: Contribution to journalArticle

49 Citations (Scopus)

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

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IMP Dehydrogenase
Inosine Monophosphate
Histone Deacetylases
Oncology
Oxidoreductases
Mycophenolic Acid
Inhibitory Concentration 50
Neoplasms
Hydroxamic Acids
Therapeutics
Cutaneous T-Cell Lymphoma
T-cells
Multiple Myeloma
Transplantation
Clinical Trials
vorinostat

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment. / Chen, Liqiang; Wilson, Daniel; Jayaram, Hiremagalur N.; Pankiewicz, Krzysztof W.

In: Journal of Medicinal Chemistry, Vol. 50, No. 26, 27.12.2007, p. 6685-6691.

Research output: Contribution to journalArticle

Chen, Liqiang ; Wilson, Daniel ; Jayaram, Hiremagalur N. ; Pankiewicz, Krzysztof W. / Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 26. pp. 6685-6691.
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