Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy

Chuang, Shuang‐En; Lee, Ying-Shuan E.; Huang, Lynn Y.L.; Chen, Chi‐Kuan; Lai, Chun‐Liang; Lin, Yu‐Hsiang; Yang, Ju‐Ying; Yang, Sheng-Chuan; Chang, Lien-Hsiang; Chen, Ching‐Hui; Liu, Chia-Wei; Lin, Her-Sheng; Lee, Yi-Ru; Huang, Kuan Pin; Fu, Kuo Chu; Jen, Hsueh-Min; Lai, Jianyu; Jian, Pei-Shiou; Wang, Yuchuan; Hsueh, Wen-Yun; Tsai, Pei-Yi; Hong, W.H.; Chang, Chia‐Chi; Wu, Diana Zc.; Wu, J.; Chen, Meng-Hsin; Yu, Kuo-Ming; Chang, Jia‐Ming; Lau, Johnson Y. N.; Huang, Jow Lay

doi:10.1016/j.ejmech.2020.112118

Cited by 13 publications

(7 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…83,84 Overexpressed Hec1 is reported in many malignancies and is associated with cancer formation, progression, and survival. 82 Accordingly, our unpublished findings suggest that overexpression of Hec1 is associated with a worse prognosis in the combined molecular subtypes survival plot for breast cancer patients. Deletions of Hec1 in tumor cell lines demonstrated its potential as a biological target by inducing mitotic abnormalities and apoptosis.…”

Section: Hec1mentioning

confidence: 82%

“…Hec1 is a spindle checkpoint regulator that is part of the conserved NDC80 complex that regulates mitotic processes. 82,83 It is responsible for recruiting checkpoint proteins to the kinetochore and ensuring proper chromosome segregation. 83,84 Overexpressed Hec1 is reported in many malignancies and is associated with cancer formation, progression, and survival.…”

Section: Hec1mentioning

confidence: 99%

“…Yet, phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function; therefore, a disruption in Hec1/Nek2 perhaps will have potential for cancer therapy. 82 Likewise, Sgo1 is phosphorylated by Nek2 for essential faithful chromosome segregation and the proper attachment of the spindle microtubule to the kinetochore. 92 This denotes the redundancy in the cell, which can be advantageous to target several kinases to improve and diversify treatment options for TNBC patients.…”

Section: Hec1mentioning

confidence: 99%

See 2 more Smart Citations

Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Colón-Marrero

Jusino

Rivera-Rivera

et al. 2021

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Biological therapies against breast cancer patients with tumors positive for the estrogen and progesterone hormone receptors and Her2 amplification have greatly improved their survival. However, to date, there are no effective biological therapies against breast cancers that lack these three receptors or triple-negative breast cancers (TNBC). TNBC correlates with poor survival, in part because they relapse following chemo- and radio-therapies. TNBC is intrinsically aggressive since they have high mitotic indexes and tend to metastasize to the central nervous system. TNBCs are more likely to display centrosome amplification, an abnormal phenotype that results in defective mitotic spindles and abnormal cytokinesis, which culminate in aneuploidy and chromosome instability (known causes of tumor initiation and chemo-resistance). Besides their known role in cell cycle control, mitotic kinases have been also studied in different types of cancer including breast, especially in the context of epithelial-to-mesenchymal transition (EMT). EMT is a cellular process characterized by the loss of cell polarity, reorganization of the cytoskeleton, and signaling reprogramming (upregulation of mesenchymal genes and downregulation of epithelial genes). Previously, we and others have shown the effects of mitotic kinases like Nek2 and Mps1 (TTK) on EMT. In this review, we focus on Aurora A, Aurora B, Bub1, and highly expressed in cancer (Hec1) as novel targets for therapeutic interventions in breast cancer and their effects on EMT. We highlight the established relationships and interactions of these and other mitotic kinases, clinical trial studies involving mitotic kinases, and the importance that represents to develop drugs against these proteins as potential targets in the primary care therapy for TNBC.

show abstract

Section: Hec1mentioning

confidence: 82%

Section: Hec1mentioning

confidence: 99%

Section: Hec1mentioning

confidence: 99%

See 1 more Smart Citation

Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Colón-Marrero

Jusino

Rivera-Rivera

et al. 2021

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

show abstract

“…In line with this, increased expression of kinetochore genes has been correlated with adverse tumor characteristics and poor prognosis, making it an attractive target for cancer therapeutics [41]. Indeed, the chemical inhibitors of the kinetochore genes AURKB [42], TTK [43], and NDC80 [44] have been proven effective in cancer therapy in preclinical studies. In addition, inhibition of ganglioside synthesis by PDMP also suppressed the gene expression of aurora kinases AURKA and AURKB.…”

Section: Discussionmentioning

confidence: 95%

Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

Qin

Dohmae

et al. 2021

Metabolites

View full text Add to dashboard Cite

The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.

show abstract

“…The compound TAI-95 also showed efficacy in treating liver cancer, as it significantly suppressed tumor growth in mice bearing human Huh-7 xenograft with oral administration. Considering the therapeutic potential of TAI-95, the compound was formulated to obtain T-1101 tosylate (Table 1, Entry 20), which not only exhibited improved oral pharmacokinetics and anti-cancer activity but also exhibited a robust synergistic anticancer effect when administered in conjunction with doxorubicin, paclitaxel, and topotecan [157]. This compound is currently being investigated in clinical trials as a potential anti-cancer therapy for sensitizing the HEC1/Nek2 axis.…”

Section: Protein-protein Interaction (Ppi) Inhibitorsmentioning

confidence: 99%

Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development

et al. 2022

View full text Add to dashboard Cite

Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.

show abstract

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy

Cited by 13 publications

References 73 publications

Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development

Contact Info

Product

Resources

About