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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 Cell death and differentiation
Vol 20
Issue 11
Date 2013 Nov
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 Clinical Trials
Mps-BAY1 Mps-BAY1 1 0
Mps-BAY2a Mps-BAY2a 1 0
Mps-BAY2b Mps-BAY2b 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Mps-BAY1 MPS1 Inhibitor 25 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 25 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 25 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
Unknown unknown colon carcinoma not applicable Mps-BAY2a + Paclitaxel Preclinical Actionable In a preclinical study, Mps-BAY2a, in combination with paclitaxel, had increased efficacy in inhibiting cell proliferation of colon carcinoma cell in culture (PMID: 23933817). 23933817
Unknown unknown colon carcinoma not applicable Mps-BAY2a Preclinical Actionable In a preclinical study, Mps-BAY2a inhibited cell cycle progression and induced cell death of colon carcinoma cells in culture (PMID: 23933817). 23933817
Unknown unknown colon carcinoma not applicable Mps-BAY1 Preclinical Actionable In a preclinical study, Mps-BAY1 inhibited cell cycle progression and induced cell death of colon carcinoma cells in culture (PMID: 23933817). 23933817
Unknown unknown colon carcinoma not applicable Mps-BAY2b Preclinical Actionable In a preclinical study, Mps-BAY2b inhibited cell cycle progression and induced cell death of colon carcinoma cells in culture (PMID: 23933817). 23933817
Unknown unknown colon carcinoma not applicable Mps-BAY1 + Paclitaxel Preclinical Actionable In a preclinical study, Mps-BAY1, in combination with paclitaxel, had increased efficacy in inhibiting cell proliferation of colon carcinoma cell in culture (PMID: 23933817). 23933817
Unknown unknown cervical cancer not applicable Mps-BAY2b + Paclitaxel Preclinical Actionable In a preclinical study, Mps-BAY2b, in combination with paclitaxel, had increased efficacy in decreasing tumor volume of cervical carcinoma xenografts (PMID: 23933817). 23933817
Unknown unknown colon carcinoma not applicable Mps-BAY2b + Paclitaxel Preclinical Actionable In a preclinical study, Mps-BAY2b, in combination with paclitaxel, had increased efficacy in inhibiting cell proliferation of colon carcinoma cell in culture (PMID: 23933817). 23933817