Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors

Padilla, Fernando; Bhagirath, Niala; Chen, Shaoqing; Chiao, Eric; Goldstein, David; Hermann, Johannes C.; Hsu, Jonathan C.; Kennedy‐Smith, Joshua J.; Kuglstatter, A.; Liao, Cheng; Liu, Wenjian; Lowrie, Lee; Luk, Kin-chun; Lynch, Stephen M.; Menke, John; Niu, Linghao; Owens, Timothy D.; O-Yang, Counde; Railkar, Aruna; Schoenfeld, Ryan C.; Slade, Michelle; Steiner, Sandra; Tan, Yun-Chou; Villaseñor, Armando G.; Wanner, Jutta; Xie, Wenwei; Xu, Daigen; Zhang, Xiaohu; Zhou, Mingyan; Lucas, Matthew C.

doi:10.1021/jm301720p

Cited by 38 publications

(25 citation statements)

References 20 publications

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“…and Wovkulich et al . reported their discovery of a novel class of pyrimidodiazepinones as potent and selective ATP‐competitive PLK1 inhibitors . RO3280 exhibits potent antiproliferative activity in a wide range of cancer cell lines, and shows strong anti‐tumour activities in an in vivo HT‐29 colorectal xenograft mouse model.…”

Section: Introductionmentioning

confidence: 99%

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Zhang

Kong

2016

J Cellular Molecular Medi

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Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. Despite improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little. In this study, the anti‐tumour activities of a novel Polo‐like kinase 1 (PLK1) inhibitor (RO3280) was evaluated in vitro and in vivo in the bladder carcinoma cell lines 5637 and T24. MTT assays, colony‐formation assays, flow cytometry, cell morphological analysis and trypan blue exclusion assays were used to examine the proliferation, cell cycle distribution and apoptosis of bladder carcinoma cells with or without RO3280 treatment. Moreover, real‐time RT‐PCR and Western blotting were used to detect the expressions of genes that are related to these cellular processes. Our results showed that RO3280 inhibited cell growth and cell cycle progression, increased Wee1 expression and cell division cycle protein 2 phosphorylation. In addition, RO3280 induced mitotic catastrophe and apoptosis, increased cleaved PARP (poly ADP‐ribose polymerase) and caspase‐3, and decreased BubR1 expression. The in vivo assay revealed that RO3280 retarded bladder cancer xenograft growth in a nude mouse model. Although further laboratory and pre‐clinical investigations are needed to corroborate these data, our demonstration of bladder cancer growth inhibition and dissemination using a pharmacological inhibitor of PLK1 provides new opportunities for future therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Zhang

Kong

2016

J Cellular Molecular Medi

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“…Water molecules were manually removed from the protein structures. Docking process was as described previously (39).…”

Section: Introductionmentioning

confidence: 99%

Curcumin suppresses stem-like traits of lung cancer cells via inhibiting the JAK2/STAT3 signaling pathway

Guo

Liang

et al. 2015

Oncology Reports

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Tumor recurrence and drug resistance are the main obstacles blocking effective treatment of cancer patients. Cancer stem cells (CSCs) have been demonstrated to be highly related to tumor recurrence and drug resistance. Thus, eliminating CSCs may be an alternative for cancer therapy. Tumor sphere formation is a functional assay to enrich the CSC-like cells. In the present study, we tested the effects of curcumin on lung cancer stem-like cells and report that in addition to inhibition on the proliferation and colony formation of lung cancer cells, curcumin reduces tumor spheres of H460 cells. Moreover, by molecular docking analysis and tumor sphere assay we discover that curcumin was able to inhibit JAK2 activity and reduce tumor spheres via inhibiting the JAK2/STAT3 signaling pathway. In a lung cancer xenograft nude mouse model, curcumin strongly repressed tumor growth. These results imply curcumin may be a potential drug in lung CSC elimination and cancer therapy.

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“…Here, two tumor cell lines, Ramos B [45] and MV4-11 [46], were used; the two tumor cell lines were chosen because their viabilities have been reported to be regulated by SYK [45,46]. Compound B4 displayed a good anti-viability potency against both Ramos B and MV4-11 cell lines with IC 50 values of 0.51 mM and 0.003 mM, respectively ( Fig.…”

Section: Functional Evaluations Of Compound B4mentioning

confidence: 99%

LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors

Yang

et al. 2015

European Journal of Medicinal Chemistry

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Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors

Cited by 38 publications

References 20 publications

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Curcumin suppresses stem-like traits of lung cancer cells via inhibiting the JAK2/STAT3 signaling pathway

LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors

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