Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain

Krzysztof Felczak, Liqiang Chen, Daniel Wilson, Jessica Williams, Robert Vince, Riccardo Petrelli, Hiremagalur N. Jayaram, Praveen Kusumanchi, Mohineesh Kumar, Krzysztof W. Pankiewicz

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K i = 5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC 50 = 0.45 μM). Compound 4 was as potent as Gleevec (IC 50 = 0.56 μM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K i's lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH.

Original languageEnglish (US)
Pages (from-to)1594-1605
Number of pages12
JournalBioorganic and Medicinal Chemistry
Issue number5
StatePublished - Mar 1 2011

Bibliographical note

Funding Information:
This research was supported by the Center for Drug Design in the Academic Health Center of the University of Minnesota and by the Veterans Affairs Merit Review Awards (HNJ).

Copyright 2012 Elsevier B.V., All rights reserved.


  • Bis(phosphonates)
  • Inhibitor design
  • Mycophenolic acid
  • NAD analogues

Fingerprint Dive into the research topics of 'Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain'. Together they form a unique fingerprint.

Cite this