CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy

Zhang, Xu; Cai, Lei; Long, Jing; Li, Jie; Wu, Lisha; Su, Juan; Jiangling, Zhang; Tao, Juan; Zhou, Jianda; Chen, Xiang; Peng, Cong

doi:10.1016/j.bcp.2019.06.014

Cited by 13 publications

(15 citation statements)

References 55 publications

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“…Molecular modeling was performed using SYBYL-X 2.1.1 from Tripos Associates Inc. Our in-house compound library composed of 111,277 purchased and synthesized compounds was used for virtual screening to find novel inhibitors of Fyn which was described as previously [19]. Crystal structure of Fyn kinase domain complexed with staurosporine obtained from the Protein Data Bank (PDB ID:2DQ7) was employed as the docking template for structure-based virtual screening using multi-precision docking.…”

Section: Molecular Dockingmentioning

confidence: 99%

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A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Cancer Cell Int

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Background: Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods: We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results: Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111,277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What's more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion: Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

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Section: Molecular Dockingmentioning

confidence: 99%

“…Subsequently, the slides incubated with primary antibody (Ki67, Abcam) overnight, and then were incubated with secondary antibody at room temperature for an hour. The slides were finally stained with DAB, counterstained with hematoxylin and mounted in neutral balsam [19].…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Cancer Cell Int

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show abstract

“…Molecular modeling was performed using SYBYL-X 2.1.1 from Tripos Associates Inc. Our in-house compound library composed of 111277 purchased and synthesized compounds was used for virtual screening to nd novel inhibitors of Fyn which was described as previously [19]. Crystal structure of Fyn kinase domain complexed with staurosporine obtained from the Protein Data Bank (PDB ID:2DQ7) was employed as the docking template for structure-based virtual screening using multi-precision docking.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…Subsequently, the slides incubated with primary antibody (Ki67, Abcam) overnight, and then were incubated with secondary antibody at room temperature for an hour. The slides were nally stained with DAB, counterstained with hematoxylin and mounted in neutral balsam [19].…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Preprint

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Background: Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods: We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results: Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What’s more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion: Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

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“…Interquartile range (IQR) comparison identified 4 of these (SYK, FAK2, GAK and RSK2 as demonstrating significant differences between TN and PT patients (Figure 5B). SYK is a recognized driver of proliferation in CLL, 36,37 while the other kinases have described roles in other tumour, [38][39][40][41] however not in the setting of CLL.…”

Section: Cell From Pt Cll Patients Show Increased Proliferative Capacitymentioning

confidence: 99%

Kinobead Profiling Reveals Reprogramming of B-cell Receptor Signaling in Response to Therapy Within Primary Chronic Lymphocytic Leukemia Cells

Linley

Griffin

Cicconi

et al. 2019

Preprint

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+44(0)151 794 5310 Running head: Therapy brings about BCR signal changes. Key points1. sIgM signaling patterns alter following in vivo therapy using either chemoimmunotherapy or ibrutinib. Kinobeads provide a novel method for high-resolution investigation of signaling in primary CLL cells. AbstractInduction of signaling via cell surface receptor activation is a critical driver of CLL pathobiology, especially via the B-cell receptor (BCR), which promotes tumor survival and progression. The vital nature of BCR signaling has been recognized through the development of kinase inhibitors (KI), most notably ibrutinib, that target key nodes within this pathway. Current efforts to monitor signaling investigate expression of a highly confined series of kinases and phosphoproteins. While generating key insights, full appreciation of their wider significance to malignant pathology and therapy response remains an unresolved issue. Here, we describe a kinobead-based protocol, used in conjunction with mass-spectrometry (MS) or immunoblotting, to study surface-IgM (sIgM) signaling within primary CLL cells. Employing this approach, we isolated a 'fingerprint' of over 30 kinases which displayed unique, patient-specific response to sIgM stimulation, and which displayed greater activation change in CLL cells from patients who had undergone prior chemoimmunotherapy (CIT) compared to those from untreated/treatment-naïve patients. Matched sample analysis of ARCTIC/AdMIRe clinical trial patients revealed the unique nature of the kinome response was present at the intra-patient level, while longitudinal profiling of IcICLLe trial patients supported this as well as showing our finding related to ibrutinib therapy. Refinement of the kinome fingerprint determined 4 kinases linked to proliferation found to be present to a significantly higher level within previously treated patient cells. Proliferation assays confirmed that these patients possess higher proliferative capacity, implying alterations of signaling resulting in promoting of biological processes critical to malignant cells. Collectively, these data represent the first comprehensive investigation into BCR signaling response within CLL, where our probing of kinase active sites reveals unique evidence of adaptive reprogramming in response to therapy.

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CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy

Cited by 13 publications

References 55 publications

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

Kinobead Profiling Reveals Reprogramming of B-cell Receptor Signaling in Response to Therapy Within Primary Chronic Lymphocytic Leukemia Cells

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