Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.

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Chen L, Gao G, Felczak K, Bonnac L, Patterson SE, Wilson D, Bennett EM, Jayaram HN, Hedstrom L, Pankiewicz KW

Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.

J Med Chem. 2007 Nov 15;50(23):5743-51. Epub 2007 Oct 24.

PubMed ID
17958343 [ View in PubMed
]
Abstract

Novel tiazofurin adenine dinucleotide (TAD) analogues 25-33 containing a substituent at C2 of the adenine ring have been synthesized as inhibitors of the two isoforms of human IMP-dehydrogenase. The 2-ethyl TAD analogue 33 [Ki = 1 nM (type I), Ki = 14 nM (type II)] was found to be the most potent. It did not inhibit three other cellular dehydrogenases up to 50 microM. Mycophenolic adenine bis(phosphonate)s containing a 2-phenyl (37) or 2-ethyl group (38), were prepared as metabolically stable compounds, both nanomolar inhibitors. Compound 38 [Ki = 16 nM (type I), Ki = 38 nM (type II)] inhibited proliferation of leukemic K562 cells (IC50 = 1.1 microM) more potently than tiazofurin (IC50 = 12.4 microM) or mycophenolic acid (IC50 = 7.7 microM).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Mycophenolic acidInosine-5'-monophosphate dehydrogenase 1Ki (nM)33825Details
Mycophenolic acidInosine-5'-monophosphate dehydrogenase 2Ki (nM)7825Details