Inhibitors of PFKFB3 for cancer therapy
Compounds used to inhibit glycolytic pathway small molecule kinase 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB) are set forth; these inhibitors can be used in the treatment of certain diseases in which cells or tumors rely on glycolytic metabolism, such as many cancer cells.
1. A method of inhibiting an isozyme of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) in a mammal; wherein the mammal has a cancer in which a PFKFB isozyme is overexpressed; said method comprising administering to the mammal an effective amount of a compound having the formula:
wherein:
X3 is —OH, and X4 is —OH;
Y is —S— or
R1 and R2 are independently selected from the group consisting of —H, and —CH 3 ; and R1 and R2 may be the same or different;
R3 is —CH 3 or —CH 2 CH 3 ; and
the configuration at the carbon-carbon double bond that is depicted in the formula between R1 and R2 is either E or Z.
2. The method of claim 1 wherein the isozyme of PFKFB is PFKFB3.
3. The method of claim 2 wherein PFKFB3 is preferentially inhibited relative to at least one other PFKFB isozyme.
4. The method of claim 1 , wherein the compound is (Z)-ethyl 3-((1,4-dihydroxynaphthalen-2-yl)thio)but-2-enoate.
5. The method of claim 1 , wherein the overexpressed isozyme is PFKFB3.