Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase

Colombo, Riccardo; Caldarelli, Marina; Mennecozzi, Milena; Giorgini, Maria Laura; Sola, Francesco; Cappella, Paolo; Perrera, Claudia; Depaolini, Stefania Re; Rusconi, Luisa; Cucchi, Ulisse; Avanzi, Nilla; Bertrand, J. A.; Bossi, R.; Pesenti, Enrico; Galvani, Arturo; Isacchi, Antonella; Colotta, Francesco; Donati, Daniele; Moll, Jürgen

doi:10.1158/0008-5472.can-10-2101

Cited by 167 publications

(224 citation statements)

References 44 publications

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“…Even in the absence of SAC activators, both classes of MPS1 inhibitors markedly increased the rate of chromosome misalignments resulting from erroneous MT-KT attachments and promoted a premature anaphase entry (i.e., before the formation of a correct equatorial metaphase plate). These results are in line with previous findings obtained with other MPS1-specific inhibitors, [8][9][10]12,15,47 upon MPS1 depletion 16,24 or following the conditional knockout of TTK, 11 confirming the central implication of this mitotic kinase in SAC function and chromosome congression. Upon exposure to MPS1 inhibitors, colorectal carcinoma cells displayed severely abnormal anaphases, and, as they progressed in mitosis, they underwent two alternative catastrophic fates: (i) they divided in a bipolar (often asymmetrical) manner, generating two aneuploid cells that most often died in the following interphase, or (ii) they failed to complete cytokinesis and hence became hyperploid.…”

Section: Discussionsupporting

confidence: 92%

“…When used at a high concentration (10 mM), Mps-BAY1, Mps-BAY2a and MpsBAY2b exhibited a restricted inhibitory effect on a panel of 220 human kinases compared with the broad-spectrum kinase inhibitors reversine and anthra[1,9-cd]pyrazole-6(2H)-one (SP600125) (Supplementary Table 2). 10,15 Of note, Mps-BAY1, Mps-BAY2a and Mps-BAY2b failed to inhibit several kinases that are known for their role in mitosis. Mps-BAY1, Mps-BAY2a and Mps-BAY2b inhibited the activation of the SAC with an IC 50 of 130 nM, 95 nM and 670 nM, respectively, as monitored in an assay in which the disappearance of histone 3 (H3) phosphorylation (a posttranslational modification occurring in prophase/metaphase) was assessed in HeLa cells responding to 300 nM nocodazole (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Some authors sustain that MPS1 inhibition/depletion neither perturbs proper chromosome orientation nor affects the correct execution of cytokinesis. 10,15,47 Conversely, it has been reported that the absence of MPS1 favors cytokinesis failure and polyploidy. 8,16,48 This discrepancy may reflect differences in the experimental models or the strategy used for MPS1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…6 Although the precise contribution of MPS1 to SAC functions remains elusive, 7 accumulating evidence suggests that MPS1 facilitates SAC activation by promoting the recruitment of SAC components to unoccupied KTs. [8][9][10][11][12][13][14][15] MPS1 has also been implicated in the so-called 'error correction mechanism', 16 a poorly characterized process that resolves the erroneous KT-MT attachments that frequently form in the early steps of mitosis. 17,18 According to current models, AURKB, one component of the chromosomal passenger complex (reviewed by Ruchaud et al 19 ), catalyzes this process by destabilizing incorrect attachments, hence generating free KTs that activate the SAC.…”

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confidence: 99%

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Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

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,5,6,11,12,13 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) 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. Mitosis is a sophisticated process that ensures the faithful inheritance of the genetic material by the cellular progeny while preventing aneuploidy and chromosomal instability (CIN), two established hallmarks of cancer. 1-3 A set of protein kinases that are collectively known as mitotic kinases, including Aurora kinases (AURKs), mitotic cyclin-dependent kinases (CDKs), Polo-like kinases and monopolar spindle 1 (MPS1), regulates and coordinates multiple aspects of chromosome segregation during mitosis. 4 MPS1 (also known as TTK) is a dual-specificity kinase (meaning that it phosphorylates both serine/threonine and tyrosine residues) with an established role in the proper alignment and orientation of chromosomes on the metaphase plate. 5 MPS1 is a core component of the spindle assembl...

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

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“…For example, inhibition of mitotic checkpoint function has been shown to cause severe chromosome segregation errors and is incompatible with human cell viability (Kops et al, 2004;Michel et al, 2004), suggesting it could represent a suitable target (Kops et al, 2005). Indeed, inhibition of the mitotic checkpoint kinase Mps1 has recently been shown to partially inhibit tumor growth in mouse models with xenografted human tumors (Colombo et al, 2010) (Table 1).…”

Section: Cin and Cancermentioning

confidence: 99%

Mitosis as an anti-cancer target

Janssen

Medema

2011

Oncogene

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Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance

Hsieh,

Du,

Yang

2023

Molecular Oncology

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Microtubule‐targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule‐targeting agents without such limitations are urgently needed. By employing a gene expression‐based drug repositioning strategy, this study identifies VU‐0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU‐0365114 exhibits a broad‐spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU‐0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU‐0365114 is not related to its original target, M5 mAChR. In addition, VU‐0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus it can overcome MDR. Furthermore, a kinome analysis shows that VU‐0365114 did not exhibit other significant off‐target effects. Taken together, our study suggests that VU‐0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.

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Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase

Cited by 167 publications

References 44 publications

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

Mitosis as an anti-cancer target

Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance

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