Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides

Laufer, Radoslaw; Ng, Grace; Liu, Yong; Patel, Narendra Kumar; Edwards, Louise; Lang, Yunhui; Li, Sze-Wan; Fehér, Miklós; Awrey, Donald E.; Leung, Genie; Beletskaya, Irina; Plotnikova, Olga; Mason, Jacqueline M.; Hodgson, Richard; Wei, Xin; Mao, Guodong; Luo, Xunyi; Huang, Ping; Green, Erin; Kiarash, Reza; Lin, Dan; Harris-Brandts, Marees; Ban, Fuqiang; Nadeem, Vincent; Mak, Tak W.; Pan, Guohua; Qiu, Wei; Chirgadze, Nickolay Y.; Pauls, Henry W.

doi:10.1016/j.bmc.2014.06.027

Cited by 36 publications

(43 citation statements)

References 49 publications

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“…Treatment with CCT271850 was well tolerated in both rounds of dosing with less than 8% body weight loss compared with the vehicle-treated controls over 15 days (Figure 5B). While this T/C is still modest, it has been shown in the literature that only moderate efficacy can be achieved in mouse models with tolerated doses of MPS1 inhibitors as single agent in the models that have been tested (Colombo et al , 2010; Tardif et al , 2011; Laufer et al , 2014; Kusakabe et al , 2015; Maia et al , 2015), indicating that combination studies with standard-of-care may lead to a more successful use of MPS1 inhibitors in clinic in this particular type of cancer.…”

Section: Resultsmentioning

confidence: 99%

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

et al. 2017

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Background:The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers.Methods:To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment.Results:CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model.Conclusions:CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.

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Section: Resultsmentioning

confidence: 99%

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

et al. 2017

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“…To date, many Mps1 inhibitors have been reported [ 17 , 22 – 30 ]. Some are studied only in vitro [ 17 , 25 , 26 , 30 ] while others have analysis extended in vivo [ 22 , 23 , 25 , 27 – 29 ]. Chemical biology analysis has limitations because inhibitors can have suboptimal properties which complicate the interpretation of experimental results (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…These complexities may be at the root of apparently contradictory Mps1 inhibitor findings. Some studies report that Mps1 inhibition is well-tolerated [ 22 , 27 , 28 ] while others report the opposite [ 25 , 29 ]. To date, no study has reported on the pathology of Mps1-targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Mitotic Checkpoint Kinase Mps1 Has a Role in Normal Physiology which Impacts Clinical Utility

et al. 2015

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Cell cycle checkpoint intervention is an effective therapeutic strategy for cancer when applied to patients predisposed to respond and the treatment is well-tolerated. A critical cell cycle process that could be targeted is the mitotic checkpoint (spindle assembly checkpoint) which governs the metaphase-to-anaphase transition and insures proper chromosomal segregation. The mitotic checkpoint kinase Mps1 was selected to explore whether enhancement in genomic instability is a viable therapeutic strategy. The basal-a subset of triple-negative breast cancer was chosen as a model system because it has a higher incidence of chromosomal instability and Mps1 expression is up-regulated. Depletion of Mps1 reduces tumor cell viability relative to normal cells. Highly selective, extremely potent Mps1 kinase inhibitors were created to investigate the roles of Mps1 catalytic activity in tumor cells and normal physiology (PF-7006, PF-3837; K i<0.5 nM; cellular IC50 2–6 nM). Treatment of tumor cells in vitro with PF-7006 modulates expected Mps1-dependent biology as demonstrated by molecular and phenotypic measures (reduced pHH3-Ser10 levels, shorter duration of mitosis, micro-nucleation, and apoptosis). Tumor-bearing mice treated with PF-7006 exhibit tumor growth inhibition concomitant with pharmacodynamic modulation of a downstream biomarker (pHH3-Ser10). Unfortunately, efficacy only occurs at drug exposures that cause dose-limiting body weight loss, gastrointestinal toxicities, and neutropenia. Mps1 inhibitor toxicities may be mitigated by inducing G1 cell cycle arrest in Rb1-competent cells with the cyclin-dependent kinase-4/6 inhibitor palbociclib. Using an isogenic cellular model system, PF-7006 is shown to be selectively cytotoxic to Rb1-deficient cells relative to Rb1-competent cells (also a measure of kinase selectivity). Human bone marrow cells pretreated with palbociclib have decreased PF-7006-dependent apoptosis relative to cells without palbociclib pretreatment. Collectively, this study raises a concern that single agent therapies inhibiting Mps1 will not be well-tolerated clinically but may be when combined with a selective CDK4/6 drug.

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“…However,b oth compoundsw ere subject to poor oral bioavailability.T he crystal structureo ft his series of compounds bound to TTK showedt hat the two nitrogen atoms of the indazole ring form two hydrogen bonds with Similarly,i ndazole-based benzenesulfonamides as potent TTK inhibitors were also reported by Laufer et al In this study, the 3-arylindazole core was obtainedt hrough as creening approach ( Figure 13). [68] Motivated by the structure of pazopanib, the sulfonamide group was introduced to providea dditional interactions with polar functionalities within the active site of TTK or engage in formation of hydrogen bonds. Preliminary studies revealed substituents at the C5 position of the indazole ring are closely relatedt oa ctivity;t hus, systematic optimization work focusing exclusively on this position was performed.…”

Section: Inhibition Of Ttkmentioning

confidence: 99%

Recent Advances in the Development of Indazole‐based Anticancer Agents

et al. 2018

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Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure-activity relationships of these compounds.

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Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides

Cited by 36 publications

References 49 publications

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

Mitotic Checkpoint Kinase Mps1 Has a Role in Normal Physiology which Impacts Clinical Utility

Recent Advances in the Development of Indazole‐based Anticancer Agents

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