Pyrrolopyrimidine Derivatives as Mps1/TTK Kinase Inhibitors for Cancer Therapy
T2014-173 Small molecules for targeted treatment of triple negative breast cancer and other aggressive phenotypes.
Breast cancer is a heterogeneous group of tumors which can be subdivided based on histopathological features, genetic alterations, and gene-expression profiles. Approximately 50-60% of all breast cancer patients and two-thirds of postmenopausal breast cancer patients have estrogen receptor positive tumors (ER+). Adjuvant hormonal therapy is the primary therapy for ER+ breast cancer. Triple negative breast cancer (TNBC) is defined by the absence of staining for estrogen receptors, progesterone receptors, and HER2/neu. Approximately 10-25% of all breast cancers diagnosed in the United States are TNBC.
Current therapies for subtypes of breast cancer, such as TNBC and other aggressive phenotypes, rely on standard chemotherapy approaches with significant side effects; therefore, newer targeted therapy approaches are needed.
A series of published studies between 2011 and 2014 have shown that Mps1 is overexpressed in breast cancer and its expression correlates with poor survival in TNBC patients. A knockdown of Mps1 RNA results in arrest of TNBC progression. Reduction in Mps1 levels results in apoptosis of cancer cells and decreased growth of the cells in vivo. Thus, Mps1 presents as a potential therapeutic target for aggressive breast cancers. At least four Mps1 inhibitors are currently in Phase I clinical trials. A team of researchers at The Ohio State University have designed, synthesized, and evaluated novel small molecule Mps1/TTK inhibitors for targeted therapies for aggressive phenotypes of breast cancer, including TNBC. In vivo studies using the lead compound show promising T1/2 and IC50 values (Sugimoto et al., Bioorg Med Chem, 2017; 25:2156-66). These small molecules may replace standard cytotoxic chemotherapies as monotherapy or be utilized in combination with current treatment regimens as safe and effective interventions.
- Pharmaceutical development for aggressive triple negative breast cancer
- Early proof of concept in several other solid tumors
- Targeted therapy
- Reduction in toxicity
- Strong anti-proliferative potential through Mps1/TTK inhibition in triple negative breast cancer and other aggressive breast cancer cell lines
- Inhibit Mps1 kinase enzymatic activity