Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors
The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: where A, B, W 1 , W 2 , W 3 , and R 1 -R 6 are described herein.
1. A method of inhibiting mutant isocitrate dehydrogenase comprising contacting a mutant isocitrate dehydrogenase having 2-hydroxyglutarate (2-HG) neomorphic activity with the compound:
under conditions effective to inhibit the neomorphic activity of the mutant isocitrate dehydrogenase.
2. The method of claim 1 , wherein the mutant isocitrate dehydrogenase is in a cell, and the method further comprises reducing 2-HG produced by the cell.
3. The method of claim 1 , wherein the neomorphic activity is R-2-HG neomorphic activity.
4. The method of claim 1 , wherein the mutant isocitrate dehydrogenase is mutant IDH1.
5. The method of claim 1 , wherein the mutant isocitrate dehydrogenase is mutant IDH1 having (R)-2-HG neomorphic activity.
6. The method of claim 1 , wherein the compound is contacted with a mutant IDH1 protein, NADPH and alpha-ketoglutarate under conditions effective to inhibit NADPH consumption.
7. The method of claim 2 , wherein the cell is a colon cancer cell.
8. The method of claim 2 , wherein the cell is a HCT116 cell.
9. The method of claim 2 , in an assay for identifying the presence of a R132 mutant IDH1 in a sample comprising the cell, the method comprising the steps of:
(a) contacting the sample comprising the cell that produces 2-HG, with the compound; and
(b) measuring an inhibition of 2-HG production in the sample with an IC 50 value of about 1 micromolar or less, to identify the sample as containing a cell having a R132 IDH1 mutation.
10. The method of claim 9 , wherein the sample comprises R132 mutant IDH1 cells.
11. The method of claim 9 , wherein the sample is obtained from a patient diagnosed with cancer.
12. The method of claim 9 , wherein the sample is contacted with the compound for about 24 hours prior to detecting the 2-HG level in the sample.
13. The method of claim 9 , wherein the sample comprises R132 mutant IDH1 cells that catalyze NADPH-dependent reduction of alpha-ketoglutarate to (R)-2-HG.
14. The method of claim 11 , wherein the patient is determined to possess an IDH1 mutation after measuring the inhibition of 2-HG production in the sample with an IC 50 value of about 1 micromolar or less, to identify the sample as containing a cell having a R132 IDH1 mutation.
15. The method of claim 14 , comprising measuring an inhibition of 2-HG production in the sample with an IC 50 value of about 0.1 micromolar or less, to identify the sample as containing a cell having a R132H IDH1 mutation.