Reference Detail

Ref Type

Journal Article

PMID

(23933817)

Authors

Jemaà M, Galluzzi L, Kepp O, Senovilla L, Brands M, Boemer U, Koppitz M, Lienau P, Prechtl S, Schulze V, Siemeister G, Wengner AM, Mumberg D, Ziegelbauer K, Abrieu A, Castedo M, Vitale I, Kroemer G

Title

Characterization of novel MPS1 inhibitors with preclinical anticancer activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell death and differentiation	20	11	2013 Nov	1532-45	Cell Death Differ

URL

Abstract Text

Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2-[(2-cyanophenyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}phenyl)-2-phenylacetamide (Mps-BAY1) (a triazolopyridine), N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(quinolin-5-yl)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2a) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence
Mps-BAY1	Mps-BAY1	0
Mps-BAY2a	Mps-BAY2a	0
Mps-BAY2b	Mps-BAY2b	4

Drug Name	Drug Classes	Drug Description
Mps-BAY1	MPS1 Inhibitor 27	Mps-BAY1, is a triazolopyridine that inhibits TTK (MPS1) to derail the spindle assembly checkpoint and induce cell cycle arrest (PMID: 23933817).
Mps-BAY2a	MPS1 Inhibitor 27	Mps-BAY2a, is an imidazopyrazine that inhibits TTK (MPS1) to derail the spindle assembly checkpoint and induce cell cycle arrest (PMID: 23933817).
Mps-BAY2b	MPS1 Inhibitor 27	Mps-BAY2b, is an imidazopyrazine that inhibits TTK (MPS1) to derail the spindle assembly checkpoint and induce cell cycle arrest (PMID: 23933817, PMID: 28539250).

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