S-trityl-L-cysteine derivative induces caspase-independent cell death in K562 human chronic myeloid leukemia cell line

Shimizu, Makiko; Ishii, Hirosuke; Ogo, Naohisa; Unno, Yuka; Matsuno, Kenji; Sawada, Jun‐ichi; Akiyama, Yasuto; Asai, Akira

doi:10.1016/j.canlet.2010.06.007

Cited by 20 publications

(8 citation statements)

References 19 publications

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“…Additionally, Eg5 has been regarded as an attractive target for cancer therapies [10]. Blocking Eg5 expression impairs the separation of duplicated centrosomes, leading to cell-cycle arrest in mitosis with monastrol microtubule arrays and triggering apoptotic cell death in tumor cells [11]. Indeed, recent studies have reported that Eg5 expression is associated with several malignancies, such as hepatic carcinoma [12], lung cancers [13], pancreatic cancer [14], gastric cancer [15], colorectal cancer [16], and prostate cancer [17].…”

Section: Introductionmentioning

confidence: 99%

Eg5 Overexpression Is Predictive of Poor Prognosis in Hepatocellular Carcinoma Patients

Liu

Zhou

et al. 2017

Disease Markers

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Eg5 (kinesin spindle protein) plays an essential role in mitosis. Inhibition of Eg5 function results in cell cycle arrest at mitosis, which leads to cell death. To date, Eg5 expression and its prognostic significance have not been studied in hepatocellular carcinoma (HCC). In this study, 26 freshly frozen HCC tissue samples and matched peritumoral tissue samples were evaluated with a one-step qPCR test and immunohistochemical (IHC) analysis was conducted on 156 HCC samples to investigate the relationships among Eg5 expression, clinicopathological factors, and prognosis. Eg5 mRNA and protein expression levels were significantly higher in HCC tissues relative to matched noncancerous tissues (p < 0.05). High Eg5 protein expression was significantly related to liver cirrhosis (p = 0.038) and TNM stage (p = 0.008). Kaplan-Meier survival and Cox regression analyses revealed that Eg5 overexpression (p = 0.001), liver cirrhosis (p = 0.009), and TNM stage (p = 0.025) were independent prognostic factors for overall survival. These findings indicate that Eg5 expression can be used as a biomarker of poor prognosis and as a novel therapeutic target for HCC.

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Section: Introductionmentioning

confidence: 99%

Eg5 Overexpression Is Predictive of Poor Prognosis in Hepatocellular Carcinoma Patients

Liu

Zhou

et al. 2017

Disease Markers

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“…The mitotic kinesin Eg5 is a promising potential therapeutic target for small molecule inhibitors and has been validated in preclinical in vivo models of cancer to be essential for the progression of mitosis. Eg5 is instrumental in forming the bipolar spindle by separation of the duplicate spindle poles in the early prometaphase stage of mitosis. , Several Eg5 and other mitotic kinesin inhibitors are at preclinical and clinical stages (reviewed in ref ), including ispinesib, one of the most advanced Eg5 inhibitors currently in multiple phase II clinical trials. − Previously, we identified S -trityl- l -cysteine (STLC) as a potent and selective inhibitor of human Eg5 (Figure , 1 ). , STLC and its derivatives induce mitotic arrest by activation of the mitotic checkpoint, which eventually leads to apoptosis in certain tumor cell lines by both caspase-dependent and -independent pathways. , Furthermore, the p- methoxy analogue 5 has recently been shown to significantly prolong survival in in vivo experiments using bladder and prostate cancer xenografts in nude mice. , As with most other allosteric Eg5 specific inhibitors, STLC binds in an allosteric pocket formed by helix α2/loop L5 and helix α3. , Initial structure–activity relationship (SAR) studies performed prior to detailed structural analysis of Eg5–STLC complexes resulted in the development of analogues with GI 50 values in the range of ∼200 nM (Figure , 2 and 3 ). , Recent investigations have identified novel analogues with improved potency in cell-based assays. , …”

Section: Introductionmentioning

confidence: 99%

Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

et al. 2012

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The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit Kiapp ≤ 10 nM and GI50 ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.

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“…15 Several STLC derivatives, such as compounds 3a and 3b with a single lipophilic para substituent in one phenyl ring of the trityl group, were 4-to 10-fold more potent than original STLC, in terms of both KSP ATPase inhibition and cell cytotoxicity. Recently, we showed that compound 3a induces mitotic arrest by activating the mitotic checkpoint, which eventually led to caspase-independent cell death in K562 chronic myeloid cells, 16 as well as demonstrated the capture of KSP in cells by using 3b immobilized on affinity beads. 17 Kozielski and co-workers, who contributed to the discovery of STLC as a KSP inhibitor, 18,19 have solved the crystal structure of KSP in complex with STLC, revealing that it binds in an allosteric loop L5 binding pocket, as is the case for most other allosteric inhibitors.…”

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confidence: 99%

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

Ogo

Ishikawa

Sawada

et al. 2015

ACS Med. Chem. Lett.

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Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle. We previously reported S-trityl-L-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo. KEYWORDS: Kinesin spindle protein, L-cysteine derivative, molecular modeling, differential scanning fluorimetry, HCT-116 xenograft model A ntimitotic agents such as microtubule stabilizers (e.g., taxanes) and destabilizers (e.g., vinca alkaloids) have been clinically validated in the treatment of multiple cancers. 1 Eribulin, which is derived from the natural product haricondolyn B, has recently been approved as a microtubule inhibitor with a new mode of action for the treatment of metastatic breast cancer.2 Microtubules play important roles throughout the cell cycle of cancer cells; however, the disruption of microtubule dynamics produces undesirable side effects, such as neurotoxicity and peripheral neuropathy, which are related to the central role tubulin plays in cell signaling and vesicular transport.3 Acquired drug resistance is another obstacle that can arise following long-term use of these agents. 4 To overcome these limitations, novel anticancer agents that do not directly act on microtubules are being developed.5 Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle.6 Inhibition of KSP leads to cell cycle arrest during mitosis and results in cells with monopolar spindles (so-called monoasters), followed by apoptosis.7 As KSP is absent in postmitotic neurons and is likely to act only in dividing cells, its inhibitors might provide better specificity than microtubule inhibitors in the treatment of human malignancies.8 A large number of KSP inhibitors with various chemical scaffolds have been reported and some of them, including ispinesib (1) and filanesib (known as ARRY-520, 2), have been entered into clinical trials (Figure 1). 9−13Although the clinical efficacy of these inhibitors has been limited to date, better results have recently been obtained in the treatment of hematological malignancies with thiadiazole-based KSP inhibitors, such as filanesib. Currently, filanesib is undergoing clinical evaluation in combination with proteasome inhibitors such as bortezomib or carfilzomib.14 Previously, we reported structure−activity relationship studies (SARs) of S-trityl-L-cysteine (STLC, 3) derivatives as KSP inhibitors (Figure 1). 15 Several STLC derivatives, such as compounds 3a and 3b with a single ...

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S-trityl-L-cysteine derivative induces caspase-independent cell death in K562 human chronic myeloid leukemia cell line

Cited by 20 publications

References 19 publications

Eg5 Overexpression Is Predictive of Poor Prognosis in Hepatocellular Carcinoma Patients

Eg5 Overexpression Is Predictive of Poor Prognosis in Hepatocellular Carcinoma Patients

Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

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