Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

Kumar, Dhiraj; Hoarau, Christophe; Bursavich, Matthew G.; Slattum, Paul M.; Gerrish, David; Yager, Kraig M.; Saunders, Michael; Shenderovich, Mark D.; Roth, Bruce L.; McKinnon, Rena; Chan, Ashley; Cimbora, Daniel; Bradford, Chad; Reeves, Leslie; Patton, Scott; Papac, Damon I.; Williams, Brandi L.; Carlson, Robert

doi:10.1016/j.bmcl.2012.04.131

Cited by 32 publications

(16 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further demonstrate in a clinically relevant animal model that intervention strategies that inhibit TTK e.g. gene silencing tools (as used in this study) or chemical compounds 29 30 31 32 33 34 35 or intracellular antibodies with blocking activity 36 37 38 39 may effectively curtail cancer cell growth and prevent future spread. Thus TTK inhibition may ultimately limit HCC development, recurrence and progression.…”

Section: Discussionmentioning

confidence: 72%

Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer

Miao

Zhang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo. Following lentiviral shRNA knockdown in several human liver cancer cell lines, we demonstrated that TTK boosts cell growth and promotes cell spreading; as well as protects against senescence and decreases autophagy. In an experimental animal model, we show that in vitro knockdown of TTK effectively blocks intrahepatic growth of human HCC xenografts. Furthermore, we note that, in vivo silencing of TTK, by systemically delivering TTK siRNAs to already tumor-bearing liver, limits intrahepatic spread of liver cancer cells. This intervention is associated with decreased tumor aggressiveness, as well as increased senescence and autophagy. Taken together, our data suggest that targeted TTK inhibition might have clinical utility as an adjunct therapy in management of liver cancer.

show abstract

Section: Discussionmentioning

confidence: 72%

Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer

Miao

Zhang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Recently, several potent MPS1 inhibitors have been developed 26,34–36 and two of them, BAY1161909 and BAY1217389, are currently in phase I clinical trials 27,37 . Our data provide a rationale for the future clinical evaluation of combined therapies utilizing TTFields and MPS1 inhibitors in patients with GBM.…”

Section: Discussionmentioning

confidence: 99%

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

View full text Add to dashboard Cite

Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200 kHz, 1.7 V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4 µM). Cells were counted after 24, 48, and 72 h of treatment and at 24 and 72 h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72 h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72 h compared to either treatment alone (−78.6% vs. TTFields, P = 0.0337; −52.6% vs. IN-3, P = 0.0205), and reduced the number of viable cells (62% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P < 0.0001). The apoptotic rate increased to 44% (TTFields 14%, P = 0.0002; IN-3 4%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92% at 72 h EOT if IN-3 treatment was continued (P = 0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.

show abstract

“…TTK kinase is associated with cell proliferation and is essential for the proper attachment of chromosomes to the mitotic spindle. Inhibition of TTK kinase has been shown to correlate with cell death caused by chromosomal missegregations [72]. Several TTK kinase inhibitors have been reported in the literature – Reversine [73], NMS-P715 [74], and MPS1-IN-1 [75].…”

Section: Resultsmentioning

confidence: 99%

A Meta Analysis of Pancreatic Microarray Datasets Yields New Targets as Cancer Genes and Biomarkers

et al. 2014

View full text Add to dashboard Cite

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a five year survival rate of less than 5%. Improved screening for earlier diagnosis, through the detection of diagnostic and prognostic biomarkers provides the best hope of increasing the rate of curatively resectable carcinomas. Though many serum markers have been reported to be elevated in patients with PC, so far, most of these markers have not been implemented into clinical routine due to low sensitivity or specificity. In this study, we have identified genes that are significantly upregulated in PC, through a meta-analysis of large number of microarray datasets. We demonstrate that the biological functions ascribed to these genes are clearly associated with PC and metastasis, and that that these genes exhibit a strong link to pathways involved with inflammation and the immune response. This investigation has yielded new targets for cancer genes, and potential biomarkers for pancreatic cancer. The candidate list of cancer genes includes protein kinase genes, new members of gene families currently associated with PC, as well as genes not previously linked to PC. In this study, we are also able to move towards developing a signature for hypomethylated genes, which could be useful for early detection of PC. We also show that the significantly upregulated 800+ genes in our analysis can serve as an enriched pool for tissue and serum protein biomarkers in pancreatic cancer.

show abstract

Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

Cited by 32 publications

References 15 publications

Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer

Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

A Meta Analysis of Pancreatic Microarray Datasets Yields New Targets as Cancer Genes and Biomarkers

Contact Info

Product

Resources

About