High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.

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Anderhub SJ, Mak GW, Gurden MD, Faisal A, Drosopoulos K, Walsh K, Woodward HL, Innocenti P, Westwood IM, Naud S, Hayes A, Theofani E, Filosto S, Saville H, Burke R, van Montfort RLM, Raynaud FI, Blagg J, Hoelder S, Eccles SA, Linardopoulos S

High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.

Mol Cancer Ther. 2019 Oct;18(10):1696-1707. doi: 10.1158/1535-7163.MCT-18-1203.

PubMed ID

31575759 [ View in PubMed

]

Abstract

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.

DrugBank Data that Cites this Article

Drugs

BOS172722

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
BOS172722	Dual specificity protein kinase TTK	Protein	Humans	Yes	Inhibitor	Details