Reference Detail

Ref Type

Journal Article

PMID

(21980130)

Authors

Tardif KD, Rogers A, Cassiano J, Roth BL, Cimbora DM, McKinnon R, Peterson A, Douce TB, Robinson R, Dorweiler I, Davis T, Hess MA, Ostanin K, Papac DI, Baichwal V, McAlexander I, Willardsen JA, Saunders M, Christophe H, Kumar DV, Wettstein DA, Carlson RO, Williams BL

Title

Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	10	12	2011 Dec	2267-75	Mol Cancer Ther

URL

Abstract Text

Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
MPI-0479605	MPI-0479605	6	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
MPI-0479605			MPS1 Inhibitor 27	MPI-0479605, an ATP-competitive inhibitor of TTK (MPS1), derails the spindle assembly checkpoint to inhibit tumor growth (PMID: 21980130).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	colon carcinoma	sensitive	MPI-0479605	Preclinical	Actionable	In a preclinical study the TTK (MPS1) inhibitor, MPI-0479605, inhibited cell cycle progression of colon carcinoma cells deficient for Tp53 with equivalent efficacy to cells with wild-type Tp53 (PMID: 21980130).	21980130
TP53 loss	colon carcinoma	sensitive	MPI-0479605	Preclinical	Actionable	In a preclinical study the TTK (MPS1) inhibitor, MPI-0479605, inhibited cell cycle progression of colon carcinoma cells deficient for Tp53 with equivalent efficacy to cells with wild-type Tp53 (PMID: 21980130).	21980130