sr-3029 and Triple-Negative-Breast-Neoplasms

Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers.

Topics: Animals; Binding Sites; Casein Kinase 1 epsilon; Casein Kinase Idelta; Catalytic Domain; Cell Line, Tumor; Female; Half-Life; Humans; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver; Molecular Docking Simulation; Permeability; Protein Kinase Inhibitors; Rats; Structure-Activity Relationship; Transplantation, Heterologous; Triple Negative Breast Neoplasms

Identification of specific drivers of human cancer is required to instruct the development of targeted therapeutics. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that casein kinase 1δ (CK1δ) is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1δ, or treatment with a highly selective and potent CK1δ inhibitor, triggers apoptosis of CK1δ-expressing breast tumor cells ex vivo, tumor regression in orthotopic models of triple-negative breast cancer, including patient-derived xenografts, and tumor growth inhibition in human epidermal growth factor receptor 2-positive (HER2(+)) breast cancer models. We also show that Wnt/β-catenin signaling is a hallmark of human tumors overexpressing CK1δ, that disabling CK1δ blocks nuclear accumulation of β-catenin and T cell factor transcriptional activity, and that constitutively active β-catenin overrides the effects of inhibition or silencing of CK1δ. Thus, CK1δ inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/β-catenin involvement.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Breast Neoplasms; Casein Kinase Idelta; Cell Proliferation; Computational Biology; Databases, Genetic; Dose-Response Relationship, Drug; Drug Design; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice, Nude; Mice, SCID; Molecular Targeted Therapy; Protein Kinase Inhibitors; Purines; RNA Interference; TCF Transcription Factors; Time Factors; Transfection; Triple Negative Breast Neoplasms; Tumor Burden; Wnt Signaling Pathway; Xenograft Model Antitumor Assays