Combination therapy with CLK/DYRK inhibitors and BCL2 inhibitors to treat leukemia
The present disclosure provides methods for treating leukemia (e.g., AML) using a CLK/DYRK inhibitor and a B-cell lymphoma 2 (BCL2) inhibitor (e.g., venetoclax). Kits for use in practicing the methods are also provided.
1 . A method for treating leukemia in a subject in need thereof comprising administering to the subject a synergistically effective amount of a CLK/DYRK inhibitor and a BCL2 inhibitor, wherein the CLK/DYRK inhibitor is selected from cirtuvivint (SM08502) or SM09419, wherein the BCL2 inhibitor is selected from venetoclax (ABT-199), navitoclax (ABT-263), or obatoclax (GX15-070), wherein the CLK/DYRK inhibitor and the BCL2 inhibitor are administered simultaneously and orally.
2 . A method for treating leukemia in a subject in need thereof comprising administering to the subject a synergistically effective amount of cirtuvivint (SM08502) and venetoclax, wherein cirtuvivint (SM08502) and venetoclax are administered simultaneously and orally.
3 . A method for treating leukemia in a subject in need thereof comprising administering to the subject a synergistically effective amount of SM09419 and venetoclax, wherein SM09419 and venetoclax are administered simultaneously and orally.
4 . The method of claim 1 , wherein the subject is resistant to BCL2 inhibitor therapy.
5 . The method of claim 2 , wherein the subject is resistant to venetoclax therapy.
6 . The method of claim 3 , wherein the subject is resistant to venetoclax therapy.
7 . The method of claim 1 , wherein the subject is resistant to combination therapy with a BCL2 inhibitor and a pyrimidine analog.
8 . The method of claim 2 , wherein the subject is resistant to combination therapy with venetoclax and a pyrimidine analog.
9 . The method of claim 3 , wherein the subject is resistant to combination therapy with venetoclax and a pyrimidine analog.
10 . The method of claim 7 , wherein the pyrimidine analog is 5-azacytidine, cytarabine, 5-fluorouracil, floxuridine, capecitabine, decitabine, or gemcitabine.
11 . The method of claim 8 , wherein the pyrimidine analog is 5-azacytidine, cytarabine, 5-fluorouracil, floxuridine, capecitabine, decitabine, or gemcitabine.
12 . The method of claim 9 , wherein the pyrimidine analog is 5-azacytidine, cytarabine, 5-fluorouracil, floxuridine, capecitabine, decitabine, or gemcitabine.
13 . The method of claim 1 , wherein the subject harbors acquired mutations in BAX, PMAIP, or TP53.
14 . The method of claim 2 , wherein the subject harbors acquired mutations in BAX, PMAIP, or TP53.
15 . The method of claim 3 , wherein the subject harbors acquired mutations in BAX, PMAIP, or TP53.
16 . The method of claim 1 , wherein the leukemia is chronic lymphocytic leukemia (CLL) or acute myeloma leukemia (AML).
17 . The method of claim 2 , wherein the leukemia is chronic lymphocytic leukemia (CLL) or acute myeloma leukemia (AML).
18 . The method of claim 3 , wherein the leukemia is chronic lymphocytic leukemia (CLL) or acute myeloma leukemia (AML).
19 . The method of claim 1 , wherein the subject is a child or an adult.