Therapeutic targeting of casein kinase 1δ in breast cancer
The invention provides a method of inhibiting casein kinase 1δ (CK1δ), comprising contacting the CK1δ with a compound of formula (I), as defined herein; such as compound SR-3029. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that CK1δ can be medically targeted in human breast cancer subtypes overexpressing this kinase. The invention further provides a method of treating cancer, such as a breast cancer, melanoma, glioblastoma, medulloblastoma, renal, bladder or colon cancer, or a cancer that metastasizes to the brain, lung, or bone provided that both elevated CK1δ and β-catenin dependence are involved in those metastatic diseases. The cancer can be a breast cancer of the triple negative subclass of breast cancers (TNBC), or can be an HER+ breast cancer.
1. A method of treating cancer, comprising administering to a patient afflicted therewith an effective dose of a compound of formula (I)
wherein
each R is independently selected hydrogen or (C 1 -C 6 )alkyl, or two R groups bonded to a nitrogen atom together with the nitrogen atom can form a 5-7 membered heterocyclyl optionally further comprising 1 or 2 heteroatoms selected from the group consisting of O, S, and NR′, wherein R′ is hydrogen or (C 1 -C 6 )alkyl;
Ar 1 is an aryl or a 5-membered or 6-membered heteroaryl, which is unsubstituted or is substituted with 1-3 independently selected halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 1 -C 6 )alkoxyl, cyano, nitro, C(═O)NR 2 , OC(═O)NR 2 , N(R)C(═O)OR, N(R)C(═O)R, or C(═O)OR;
Het 1 is a monocyclic or bicyclic heteroaryl, which is unsubstituted or is substituted with 1-3 independently selected halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 1 -C 6 )alkoxyl, cyano, nitro, C(═O)NR 2 , OC(═O)NR 2 , N(R)C(═O)OR, N(R)C(═O)R, or C(═O)OR;
or a pharmaceutically acceptable salt thereof;
wherein the cancer is a cancer with upregulated expression levels of both CK1δ and β-catenin; and
wherein the breast cancer is of the triple negative subclass of breast cancers (TNBC) or is an HER+ breast cancer.
2. The method of claim 1 , wherein the compound of formula (I) is SR-3029
or a pharmaceutically acceptable salt thereof.