Inhibitors of polyisoprenylated methylated protein methyl esterase
View Patent ↗Inhibitors of the enzyme prenylated methylated protein methyl esterase (PMPMEase), the last step in the prenylation process for many eukaryotic proteins, having the general structure R 1 -X-A-B(R 2 )-Y or R 1 -X-A(R 2 )-B-Y, where R 1 is preferably a polyisoprenyl group, X is a linking group, Y is a group that promotes affinity interactions to the active site of PMPMEase and imparts hydrolysis resistance to the inhibitor, A and B are bridge atoms, and R 2 is a characteristic-providing substituent.
1. An inhibitor of the enzyme prenylated methylated protein methyl esterase (PMPMEase), which has the formula
where R 1 is a group selected from substituted or unsubstituted prenyl or polyisoprenyl;
X is a linking group;
the two atoms between the X and Y groups are the bridge and are selected from C, N, O, and S;
R 2 is a group selected to impart increased aqueous solubility or potency, and includes an open chain alkyl, alicyclic, aryl, or aryloxy group containing one or more salt-forming basic or acidic groups separated from the bridge by a tether; and
Y is selected from
where R 3 is alkyl, substituted alkyl, aryl, substituted aryl, SR 5 , OR 5 (except carboxyl esters), NHR 5 or NR 5 R 6 , R 4 is alkyl, substituted alkyl, aryl or substituted aryl and R 5 and R 6 are alkyl, substituted alkyl, aryl or substituted aryl; and
wherein if Y is
and the bridge atoms are both C then R 3 is not OR 5 .
2. The inhibitor of claim 1 , wherein R 1 is a substituted or unsubstituted trans,trans-farnesyl or an all trans-geranylgeranyl group.
3. The inhibitor of claim 1 , wherein X is S, Se, SO, SO 2 , O, NH, NR, or CH 2 .
4. The inhibitor of claim 1 , wherein R 2 substitutes the polypeptide portion of an endogenous protein substrate.
5. The inhibitor of claim 1 , wherein the salt forming basic or acidic group is selected from the group consisting of amino, carboxylic acid, sulfonic, and phosphoric.
6. The inhibitor of claim 1 , wherein Y imparts selectivity between PMPMEase isoforms.