Pyrrolopyrimidine Derivatives as Mps1/TTK Kinase Inhibitors for Cancer Therapy

Small molecules for targeted treatment of triple negative breast cancer and other aggressive phenotypes.

The Need

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.

The Technology

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. Mps1 activates the spindle assembly checkpoint to ensure faithful segregation of chromosmomes during mitosis. In cancers, chromosomal instability is common, and Mps1 upregulation prevents mitotic catastrophe due to severe aneuploidy. This allows the cancer to survive. Pharmacalogical inhibition of Mps1 causes severe defects in chromosomal segregation, causing catastrophic levels of aneuploidy. This 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). Futher, oral bioavailability in mice was 59% with a brain to plasma ratio of 0.2. In vitro funcitnal assays confirm that the lead compound disrupts the proper functioning of the spindle assembly checkpoint and decreases centriole duplication. Tumor-bearing mice dosed daily for six weeks with an efficacious dose of our lead compound exhibited no adverse effects on body weight. These small molecules may replace standard cytotoxic chemotherapies as monotherapy or be utilized in combination with current treatment regimens as safe and effective interventions.

Commercial Applications

  • Pharmaceutical development for aggressive triple negative breast cancer
  • Early proof of concept in several other solid tumors

Benefits/Advantages

  • 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

Loading icon