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      Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein–protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells

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          Abstract

          Triple-negative breast cancer (TNBC) is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes. The epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) have been proposed as important mechanisms underlying TNBC metastasis. CDK9 is highly expressed in breast cancer, including TNBC, where it promotes EMT and induces cancer cell stemness. In this study, we have identified a tetrahydroisoquinoline derivative (compound 1) as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening. Interestingly, by targeting the ATP binding site, compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 protein–protein interaction (PPI). Mechanistically, compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction, leading to reduced TNBC cell proliferation and migration. To date, compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1. Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents. Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

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          Most cited references56

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          The basics of epithelial-mesenchymal transition.

          The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
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            The epithelial-mesenchymal transition generates cells with properties of stem cells.

            The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers. Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells. Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties.
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              Kinase-targeted cancer therapies: progress, challenges and future directions

              The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                10 July 2021
                November 2022
                10 July 2021
                : 9
                : 6
                : 1674-1688
                Affiliations
                [a ]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, PR China
                [b ]Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, PR China
                [c ]Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, PR China
                [d ]Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, PR China
                Author notes
                []Corresponding author. duncanleung@ 123456um.edu.mo
                [∗∗ ]Corresponding author. edmondma@ 123456hkbu.edu.hk
                [1]

                These authors contributed equally to this work.

                Article
                S2352-3042(21)00086-6
                10.1016/j.gendis.2021.06.005
                9485199
                36157485
                5cae3fab-756e-4af5-99fc-ec90ea0fa2d4
                © 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 12 March 2021
                : 31 May 2021
                : 7 June 2021
                Categories
                Full Length Article

                cancer stem cells,cdk9-cyclin t1,epithelial mesenchymal transition,protein–protein interaction (ppi),triple-negative breast cancer (tnbc)

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