Methods for treating leukemia and disorders mediated by CBFβ and RUNX1 proteins
A method for treating core binding factor (CBF) leukemia in a subject, comprising administering to a subject having CBF leukemia a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or ester thereof, that inhibits CBFβ and RUNX1 binding in the subject, thereby treating the CBF leukemia.
1. A method for treating core binding factor (CBF) leukemia in a subject, comprising administering to a subject having CBF leukemia a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or ester thereof, selected from:
wherein each R 1 is individually halogen; R 2 is pyrrolyl; and a is 0 to 4;
wherein each R 1 is halogen; R 2 is pyrrolyl; and a is 0 to 4; or
wherein each R 1 is halogen; R 2 is pyrrolyl; R 3 is lower alkyl; and a is 0 to 4; or
2. The method of claim 1 , further comprising co-administering the compound with a chemotherapeutic agent.
3. The method of claim 2 , wherein the chemotherapeutic agent is selected from cytarabine, an anthracycline, all-trans-retinoic acid (ATRA), histamine dihydrochloride, interleukin-2, getuzumab ozogamicin, clofarabine, or a combination thereof.
4. The method of claim 1 further comprising co-administering the compound with a kinase inhibitor.
5. The method of claim 1 , wherein the compound is selected from:
6. The method of claim 1 , wherein the compound is:
7. The method of claim 1 , wherein the compound is:
8. The method of claim 1 , wherein the compound is:
9. The method of claim 1 , wherein the compound is:
10. The method of claim 1 , wherein the CBF leukemia is selected from acute myeloid leukemia mediated by a CBFβ-MYH11 fusion gene, acute myeloid leukemia mediated by a RUNX1-ETO fusion gene, or acute lymphoid leukemia mediated by a TEL-RUNX1 fusion gene.
11. A method for inhibiting interaction between CBFβ and RUNX1 in a cell, comprising contacting the cell with a compound, or a pharmaceutically acceptable salt or ester thereof, selected from:
12. The method of claim 11 , wherein inhibiting interaction between CBFβ and RUNX1 in a cell inhibits formation of at least one of the following: CBFβ-MYH11 fusion gene, RUNX1-ETO fusion gene, or TEL-RUNX1 fusion gene.
13. A pharmaceutical composition comprising:
(i) at least one compound, or a pharmaceutically acceptable salt or ester thereof, selected from:
and
(ii) at least one chemotherapeutic agent suitable for treating leukemia, or a pharmaceutically acceptable salt thereof.