title: Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain.
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.
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Felczak
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Wilson
authors.forename: Jessica
authors.initials: J
authors.lastname: Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.forename: Hiremagalur N
authors.initials: HN
authors.lastname: Jayaram
authors.forename: Praveen
authors.initials: P
authors.lastname: Kusumanchi
authors.forename: Mohineesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D011756:Diphosphates / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D011756:Diphosphates; D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase