NTRC has developed a series of very potent and highly selective inhibitors of the spindle assembly checkpoint kinase TTK, and has identified a genomic biomarker that predicts sensitivity of tumor cells to TTK inhibition.
The dual-specificity protein kinase TTK, commonly referred to as Mps1, is a component of the spindle assembly checkpoint, a surveillance mechanism that ensures the fidelity of chromosome segregation. Inhibition of TTK kinase activity with small molecule kinase inhibitors leads to chromosome segregation errors by allowing mitotic exit in the presence of unattached kinetochores. After several rounds of cell division, the accumulation of chromosome segregation errors results in cancer cell death by apoptosis. Several TTK inhibitors have been shown to reduce the growth of tumors in xenograft models of human cancer. In a collaboration with the Netherlands Cancer Institute in Amsterdam, it was shown that the small molecule kinase inhibitor NTRC 0066-0, discovered and designed at NTRC, can increase the efficacy of taxane chemotherapy in a BRCA-deficient model of triple-negative breast cancer, the most aggressive type of breast cancer .
Target residence time-guided optimization of NTRC 0066-0 resulted in TTK kinase inhibitors with sub-nanomolar affinity for TTK, exquisite selectivity over the kinome, and potent anti-proliferative activity in cell-based proliferation assays, rivaling classical chemotherapy . NTRC scientists showed that cancer cell lines with relatively stable genomes are relatively more sensitive to TTK inhibition than chromosomally unstable cells . Moreover, NTRC scientists discovered that tumors that harbor an oncogenic mutation in CTNNB1, the gene encoding for the cancer driver β-catenin, are particularly sensitive to TTK inhibitors . This synthetic lethal interactions forms a biologic basis for a TTK-based anti-cancer therapy with a favorable therapeutic index.
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NTRC inhibitor NTRC 1501-0 induces regression of tumor growth in a xenograft model of a human cancer cell line homozygous for mutant CTNNB1.
NTRC publications on TTK
 Maia et al. (2015) Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model. Annals of Oncology 26, 2180–2192.
 Uitdehaag et al. (2017) Target residence time-guided optimization on TTK kinase results in inhibitors with potent anti-proliferative activity. Journal of Molecular Biology 429, 2211-2230.
 Libouban et al. (2017) Stable aneuploid tumor cells are more sensitive to TTK inhibition than chromosome unstable cell lines. Oncotarget 8, 38309-38325.
 Zaman et al. (2017) TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers. Molecular Cancer Therapeutics 16, 2609-2617.
NTRC patents on TTK
de Man et al. (2015) (5,6-dihydro)pyrimido[4,5-E]indolizines. WO 2015/155042 A1.
de Roos et al. (2016) Prognostic biomarkers for TTK inhibitor chemotherapy. WO 2016/166255 A1.