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 journalArticle

21 Scopus citations

Abstract

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
Volume19
Issue number5
DOIs
StatePublished - Mar 1 2011

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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    Felczak, K., Chen, L., Wilson, D., Williams, J., Vince, R., Petrelli, R., Jayaram, H. N., Kusumanchi, P., Kumar, M., & Pankiewicz, K. W. (2011). Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain. Bioorganic and Medicinal Chemistry, 19(5), 1594-1605. https://doi.org/10.1016/j.bmc.2011.01.042