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

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Chen L, Wilson D, Jayaram HN, Pankiewicz KW

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

J Med Chem. 2007 Dec 27;50(26):6685-91. Epub 2007 Nov 27.

PubMed ID

18038969 [ View in PubMed

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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 (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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mycophenolic acid	Inosine-5'-monophosphate dehydrogenase 1	Ki (nM)	40	N/A	N/A	Details
Mycophenolic acid	Inosine-5'-monophosphate dehydrogenase 2	Ki (nM)	10	N/A	N/A	Details