The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer

Kandil, Sahar; Prencipe, Filippo; Jones, Samuel; Hiscox, Stephen Edward; Westwell, Andrew D.

doi:10.1111/cbdd.13083

Cited by 6 publications

(3 citation statements)

References 20 publications

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“…However, C4 displays its anticancer activity at a remarkably high micromolar concentration (>100 μM). Our previous lead optimisation work on the chemical structure of chloropyramine (C4) led to the identification of a more active analogue against three human breast cancer lines (MDA-MB-231, BT474, and T47D) with an average antiproliferative activity (IC 50 ) of approximately 23 μM [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer

et al. 2020

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Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer

et al. 2020

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“…C4 inhibits FAK activity by hampering the interaction of the C-terminus region of FAK and is currently developed with preclinical experiments [ 82 ] C4 treatment resulted in FAK inactivation, reduced cell viability and proliferation, cell cycle arrest and apoptosis in pancreatic cancer cells. Mechanismly, C4 highly specific disrupt FAK-VEGFR3 interactions resulted in cell cycle arrest [ 83 ].…”

Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

Focal adhesion kinase inhibitors, a heavy punch to cancer

et al. 2021

Discov Onc

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Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

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“…The survival of breast cancer patients has been significantly increased in recent years by improvements in surgical treatment, radiotherapy, chemotherapy, and endocrine therapy. However, the efficacy is not yet ideal for triple negative breast cancer (1). At present, molecule-targeted therapy is a hot topic in the treatment of breast cancer (2).…”

Section: Introductionmentioning

confidence: 99%

Silencing SCAMP1-TV2 Inhibited the Malignant Biological Behaviors of Breast Cancer Cells by Interaction With PUM2 to Facilitate INSM1 mRNA Degradation

Wei

Zheng

et al. 2020

Front. Oncol.

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Background: Molecular-targeted therapy plays an important role in the combined treatment of breast cancer. Long noncoding RNA (LncRNA) plays a significant role in regulating breast cancer progression. The present study is to reveal the potential roles and molecular mechanism that the secretory carrier-associated membrane protein 1-transcript variant 2 (SCAMP1-TV2) has in breast. Methods: Cell Counting Kit-8 (CCK-8), RNA Immunoprecipitation (RIP), and RNA pull-down assays were employed to determine the interactions between SCAMP1-TV2 and Pumilio RNA binding family member 2 (PUM2). The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were used to get to know the effect of human insulinoma-associated 1 (INSM1) directly on the SAM and SH3 domain containing 1 (SASH1) promoter. Results: Silenced SCAMP1-TV2 inhibited the proliferation, migration, and invasion of breast cancer cells, and promoted cell apoptosis. Meanwhile, SCAMP1-TV2 downregulation decreased its binding to PUM2 and increased the binding of PUM2 to INSM1 messenger RNA (mRNA), thus promoting the degradation of INSM1 mRNA. Silencing INSM1 decreased its inhibitory effect on SASH1 transcription and inhibited the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. The xenograft tumor growth in a nude mice was significantly inhibited by the silencing of SCAMP1-TV2 in combination with the overexpression of PUM2. Conclusions: SCAMP1-TV2/PUM2/INSM1 pathway plays an important role in regulating the biological behavior of breast cancer cells.

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The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer

Cited by 6 publications

References 20 publications

Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer

Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer

Focal adhesion kinase inhibitors, a heavy punch to cancer

Silencing SCAMP1-TV2 Inhibited the Malignant Biological Behaviors of Breast Cancer Cells by Interaction With PUM2 to Facilitate INSM1 mRNA Degradation

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