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.

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 chromosomes during mitosis. In cancer, chromosomal instability is common and Mps1 upregulation prevents mitotic catastrophe due to severe aneuploidy, which allows the cancer to survive.

Pharmacological 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. Recent studies discussed below show that Compound 13 is another potential clinical candidate for companies to consider.

The Technology

A team of researchers at The Ohio State University designed, synthesized, and evaluated various candidate compounds in anti-proliferative assays and selected Compound 13 as the lead compound. In vivo studies using daily intraperitoneal (ip) dosing of Compound 13 showed promising T1/2 and IC50 values (Sugimoto et al., Bioorg Med Chem, 2017; 25:2156-66). Additional studies also showed that Compound 13 is orally bioavailable and brain penetrant in mice. In vitro functional assays confirmed that Compound 13 disrupted the proper functioning of the spindle assembly checkpoint and decreased centriole duplication. Tumor-bearing mice dosed daily for six weeks with an efficacious dose of Compound 13 exhibited no adverse effects on body weight. More specifically, Compound 13 showed significant decreased tumor growth. The totality of these studies show that Compound 13 is worthy of further investigation as a potential targeted therapy for TNBC in both single agent and combination therapy settings.

Commercial Applications

• Pharmaceutical development for targeted therapy for triple negative breast cancer in both single agent and combination therapy settings

Benefits/Advantages

• Targeted therapy that demonstrates tumor growth delay with no body weight decrease in a preclinical TNBC model
• Strong anti-proliferative potential through Mps1/TTK inhibition in triple negative breast cancer
• Inhibit Mps1 kinase enzymatic activity

Patent Status

• US Patent 10,611,765