Chromosomal instability is a hallmark of cancer cells. Enhancing chromosomal instability by targeting the mitotic checkpoint selectively kills tumor cells. NTRC has developed best-in-class inhibitors of the mitotic checkpoint kinase TTK.

The protein kinase TTK (commonly referred to as Mps1) is a component of the mitotic checkpoint, a machinery that ensures the fidelity of sister chromatid segregation over two daughter cells during cell division. Defects or inhibition of the mitotic checkpoint leads to aneuploidy, an abnormal number of chromosomes. Whereas during embryonic development the vast majority of single segregation errors is not tolerated, aneuploidy is a common genetic alteration in solid human tumors and a predictor of poor prognosis in breast, lung, brain and colorectal cancer. TTK expression is increased in breast cancer with chromosomal instability and in particular in triple negative breast cancer, the most aggressive type of breast cancer. Inhibition of TTK activity results in chromosome mis-segregation (see Figure) and death of cancer cells. Normal cells are less sensitive to TTK inhibition, providing the biologic basis for a selective anti-cancer therapy with a favorable therapeutic index.

Figure. Chromosomes of dividing tumour cells lined up in the metaphase plate. Treatment with TTK inhibitor results in chromosome mis-segregation (indicated by red circles)

NTRC has developed best-in-class inhibitors of TTK. The compounds inhibit TTK enzyme activity with sub-nanomolar potency. The compounds show very potent anti-proliferative activity on a broad panel of cancer cell lines and are highly selective over other kinases. The compounds have good oral bioavailability and drug-like properties. In collaboration with investigators of the Netherlands Cancer Institute in Amsterdam, NTRC has validated the concept that inhibition of TTK sensitizes tumors to treatment with antimitotic drugs in a model for hereditary breast cancer. If you are interested to learn more about this project, contact us.

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