Use of ITK inhibitors for the treatment of cancer
This invention relates generally to the use of ITK (IL-2 inducible T-cell kinase) inhibitors for the treatment of patients who have melanoma or other solid tumors. Applicants demonstrate that ITK lentiviral small hairpin RNA knockdowns and a small molecule inhibitor can each decrease the proliferation and migration of melanoma cell lines and a small molecule inhibitor can be used to inhibit the growth of melanomas in vivo.
1. A method of inhibiting the growth of a solid tumor in a subject which comprises administering an effective amount of a selective interleukin-2 inducible T-cell kinase (ITK) inhibitor to the subject wherein the selective ITK inhibitor is a benzimidazole having the formula
R is alkenyl, alkoxy, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, halogen, hydroxyl, heteroaryl, heterocycloalkyl, or nitro;
R 1 is alkenyl, alkyl, alkyl(aryl), alkynyl, aryl, heteroaryl, or heterocycloalkyl; and
R 2 is alkenyl, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, hydroxyl, heterocycloalkyl, nitro, thiophenyl cycloalkyl, thiophenyl heteroaryl, or thiophenyl heterocycloalkyl.
2. The method of claim 1 , wherein the solid tumor is a breast, a gastric, a head and neck, a kidney, a liver, a lung, a melanoma, a non-small cell lung cancer (NSCLC), a pancreatic, or a uterine tumor.
3. The method of claim 2 , wherein the melanoma tumor is a primary melanoma tumor.
4. The method of claim 2 , wherein the melanoma tumor is a melanoma metastasis tumor.
5. The method of claim 2 , wherein the breast tumor is an estrogen receptor negative (ER(−)) or a progesterone receptor negative (PR(−)) breast tumor.
6. The method of claim 1 , wherein the benzimidazole is
R is alkenyl, alkoxy, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, halogen, heteroaryl, or heterocycloalkyl;
R 1 is alkyl, alkyl(aryl), alkynyl, aryl, heteroaryl, or heterocycloalkyl; and
R 2 is alkenyl, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, thiophenyl cycloalkyl, thiophenyl heteroaryl or thiophenyl heterocycloalkyl.
7. The method of claim 6 , wherein the benzimidazole is
R is alkyl, alkyl(aryl), amino, heteroaryl, or heterocycloalkyl;
R 1 is alkyl; and
R 2 is aryl, heteroaryl, heterocycloalkyl, thiophenyl cycloalkyl, thiophenyl heteroaryl or thiophenyl heterocycloalkyl.
8. The method of claim 7 , wherein the benzimidazole is
9. A method of inhibiting melanoma cell motility in a subject which comprises administering an effective amount of a selective interleukin-2 inducible T-cell kinase (ITK) inhibitor to the subject wherein the selective ITK inhibitor is a benzimidazole having the formula
R is alkenyl, alkoxy, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, halogen, hydroxyl, heteroaryl, heterocycloalkyl, or nitro;
R 1 is alkenyl, alkyl, alkyl(aryl), alkynyl, aryl, heteroaryl, or heterocycloalkyl; and
R 2 is alkenyl, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, hydroxyl, heterocycloalkyl, nitro, thiophenyl cycloalkyl, thiophenyl heteroaryl, or thiophenyl heterocycloalkyl.
10. A method of maintaining a cell in a GO/G1 cell cycle which comprises administering to the cell an effective amount of a selective interleukin-2inducible T-cell kinase (ITK) inhibitor wherein the selective ITK inhibitor is a benzimidazole having the formula
R is alkenyl, alkoxy, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, halogen, hydroxyl, heteroaryl, heterocycloalkyl, or nitro;
R 1 is alkenyl, alkyl, alkyl(aryl), alkynyl, aryl, heteroaryl, or heterocycloalkyl; and
R 2 is alkenyl, alkyl, alkyl(aryl), alkynyl, amino, aryl, cycloalkyl, hydroxyl, heterocycloalkyl, nitro, thiophenyl cycloalkyl, thiophenyl heteroaryl, or thiophenyl heterocycloalkyl.