SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS
1 Assignment
0 Petitions
Accused Products
Abstract
The invention provides methods for modulating, e.g., antagonizing, the activity of the Hedgehog signaling pathway, and for treating Hedgehog related disorders such as cancers (e.g., medulloblastoma). In particular, the invention provides methods for inhibiting aberrant growth states resulting from phenotypes such as Ptch loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function by administering to a mammal combinations of Smoothened inhibitors (e.g., a compound of Formula I, Formula II, or Formula III, or any of the compounds listed herein or incorporated by reference) and cholesterol biosynthesis pathway inhibitors (e.g., statins), Gli inhibitors, and/or Phosphatidylinositol 3-kinase (PI3K) inhibitors.
-
Citations
45 Claims
-
1-32. -32. (canceled)
-
33. A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a PI3 kinase inhibitor, wherein the Smoothened inhibitor is 2-methyl-4′
- -trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′
-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof. - View Dependent Claims (34, 35, 36)
- -trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′
-
37. A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a Gli inhibitor, wherein the Smoothened inhibitor is 2-methyl-4′
- -trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide or 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′
-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof. - View Dependent Claims (38, 39, 40, 41)
- -trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide or 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′
-
42. A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a statin, wherein the Smoothened inhibitor is 2-methyl-4′
- -trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′
-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof. - View Dependent Claims (43, 44, 45)
- -trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′
Specification