A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor

Xing, Naidong; Ding, Sentai; Saito, Ryoichi; Nishizawa, Koji; Kobayashi, Takashi; Inoue, Takahiro; Oishi, Shinya; Fujii, Nobutaka; Lv, Jia-Jv; Ogawa, Osamu; Nishiyama, Hiroyuki

doi:10.1038/aja.2010.171

Cited by 18 publications

(19 citation statements)

References 32 publications

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“…These agents cause arrest of mitosis by damaging monopolar spindle and consequently causing cell death [7]; some cells treated with kinesin inhibitors arrest in G1-like phase and die for apoptosis by a specific tetraploidy checkpoint [8]. The negative regulation of Eg5 is capable to arrest the replication of hepatocellular carcinoma [9], glioblastoma [10] and prostate cancer cells [11] in vitro, suggesting that Eg5 inhibition can be a potential target for anti-cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Several compounds that inhibit kinesins have been studied in clinical trials [12,13], unfortunately with poor benefits, in opposite to successful results obtained in pre-clinical research on neoplastic cells [9][10][11]. Among Eg5-inhibitors, ispinesib has been shown to share the mode of action with monastrol [14], however its clinical utilization led to conflicting results.…”

Section: Introductionmentioning

confidence: 99%

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The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

et al. 2016

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Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

et al. 2016

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“…Recent studies indicate that Eg5 may also play a role in intracellular transport in the cytoplasm, suggesting that Eg5-inhibitors may target Eg5 expressing non-mitotic cells too [ 16 ; 17 ]. Xing et al analyzed archival specimens from 80 patients with clinically localized PCa; half stained positive for Eg5, while benign prostate cells did not express Eg5 [ 18 ]. Considering the low mitotic index of PCa cells regardless of disease stage [ 19 ], these data suggest that Eg5 may indeed be expressed in non-mitotic PCa cells too [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness

et al. 2014

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Novel biomarkers predicting prostate cancer (PCa) aggressiveness and docetaxel therapy response of PCa patients are needed. In this study the correlation between nuclear Eg5-expression, PCa docetaxel response and PCa aggressiveness was assessed. Immunohistochemical staining for nuclear Eg5 was performed on 117 archival specimens from 110 PCa patients treated with docetaxel between 2004 and 2012. Samples were histologically categorized as positive/negative.Median follow-up time from diagnosis was 11.6 years. Nuclear Eg5-expression was significantly related to docetaxel response (p=0.036) in tissues acquired within three years before docetaxel initiation. Nuclear Eg5-expression was not related to Gleason-score (p=0.994). Survival of patients after docetaxel initiation did not differ based on nuclear Eg5-expression (p=0.540). Analyzing samples taken before hormonal therapy, overall survival and time to docetaxel use were significantly decreased in patients with nuclear Eg5-expressing tumors (p<0.01). Eg5-positive nuclei were found more frequently in T4-staged tumors (p=0.04), Gleason 8-10 tumors (p=0.08), and in metastasized tumors (p<0.01). Multivariate analyses indicated that nuclear Eg5-expression may be an independent parameter for tumor aggressiveness. Limitations of a retrospective analysis apply.In conclusion, nuclear Eg5-expression may be a predictive biomarker for docetaxel response in metastatic castrate-resistant PCa patients and a prognostic biomarker for hormone-naive PCa patients. Prospective validation studies are needed.

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“…20 Antitumor activity has been reported for 4 and the p -methoxyphenyl analogue 7 across leukemia, bladder, and prostate xenograft models. 21−23 In initial SAR investigations, analogues with improved cellular potency were identified which incorporated a phenyl containing lipophilic para substituents (e.g., 5 – 7 , Figure 2). 24−26 The subsequent elucidation of the crystal structure of 4 in complex with Eg5 27,28 enabled us to pursue the rational SAR-based optimization of this scaffold, which led to the development of butanamine analogues with improved activity against Eg5 ( 11 – 14 , Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

et al. 2013

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The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-l-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (Kiapp < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

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A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor

Cited by 18 publications

References 32 publications

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

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