Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance

Fischer, Tim; Najjar, Abdulkarim; Totzke, Frank; Schächtele, Christoph; Sippl, Wolfgang; Hilgeroth, Andreas

doi:10.1080/14756366.2017.1370583

Cited by 15 publications

(3 citation statements)

References 24 publications

(26 reference statements)

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“…Additionally, it may also be possible to “sensitize” cells to antiangiogenic treatment by lowering the tumor cell survival threshold through suppressing EGFR signaling pathways [116]. Subsequently, a dual suppression of both PDGFR and EGFR may be preferable to prevent a kinase inhibitor resistance led by a receptor heterodimerization [120].…”

Section: Opportunities Of Targeting Platelets In Cancer Treatmentmentioning

confidence: 99%

The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells

Huong

Nguyen

et al. 2019

Cancers

111

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Besides the critical functions in hemostasis, thrombosis and the wounding process, platelets have been increasingly identified as active players in various processes in tumorigenesis, including angiogenesis and metastasis. Once activated, platelets can release bioactive contents such as lipids, microRNAs, and growth factors into the bloodstream, subsequently enhancing the platelet–cancer interaction and stimulating cancer metastasis and angiogenesis. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated to be associated with platelets. Therefore, understanding how platelets contribute to the tumor microenvironment may potentially identify strategies to suppress cancer angiogenesis, metastasis, and drug resistance. Herein, we present a review of recent investigations on the role of platelets in the tumor-microenvironment including angiogenesis, and metastasis, as well as targeting platelets for cancer treatment, especially in drug resistance.

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Section: Opportunities Of Targeting Platelets In Cancer Treatmentmentioning

confidence: 99%

The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells

Huong

Nguyen

et al. 2019

Cancers

111

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“…Their potential in modulating corneal fibrosis remains an area of active research [183][184][185]. Dual inhibitors targeting both the TGF-β and EGFR pathways simultaneously represent another exciting avenue [186,187]. These drugs aim to offer a broader spectrum of action by dampening the synergistic effects of both pathways, thereby minimizing the risk of excessive fibrosis during corneal wound repair [188].…”

Section: Therapeutic Targets For Tgf-β Signaling Based Therapiesmentioning

confidence: 99%

TGF-β-Based Therapies for Treating Ocular Surface Disorders

Ogata,

Verma,

Coulson-Thomas

et al. 2024

Cells

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The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-β), a versatile signaling molecule that coordinates various cell responses, has a central role in corneal wound healing. Upon corneal injury, TGF-β is rapidly released into the extracellular environment, triggering cell migration and proliferation, the differentiation of keratocytes into myofibroblasts, and the initiation of the repair process. TGF-β-mediated processes are essential for wound closure; however, excessive levels of TGF-β can lead to fibrosis and scarring, causing impaired vision. Three primary isoforms of TGF-β exist—TGF-β1, TGF-β2, and TGF-β3. Although TGF-β isoforms share many structural and functional similarities, they present distinct roles in corneal regeneration, which adds an additional layer of complexity to understand the role of TGF-β in corneal wound healing. Further, aberrant TGF-β activity has been linked to various corneal pathologies, such as scarring and Peter’s Anomaly. Thus, understanding the molecular and cellular mechanisms by which TGF-β1-3 regulate corneal wound healing will enable the development of potential therapeutic interventions targeting the key molecule in this process. Herein, we summarize the multifaceted roles of TGF-β in corneal wound healing, dissecting its mechanisms of action and interactions with other molecules, and outline its role in corneal pathogenesis.

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“…27 The binding geometries of SIQ17 in the ATP-binding site reveal that its sulfonyl group is mainly stabilized by the conserved residue C797 via weak hydrogen bonding (see two-dimensional (2D) interaction in Figure 5), and an additional residue, L718, partially contributes to such binding via interactions with the sulfonyl group of SIQ17 (Figure 5). The contributions from L718, E762, and T854 residues have also been identified in previously reported EGFR-TK inhibitors such as chalcones, 28 anilino-1,4-naphthoquinones, 29 pyrimido[4,5-b]indoles, 30 and lycorine. 31 2.5.…”

Section: Ct+mixmentioning

confidence: 99%

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors

et al. 2023

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The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9−13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC 50 values of ca. 0.6−10.2 nM) compared to the known drug erlotinib (IC 50 of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.

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Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance

Cited by 15 publications

References 24 publications

The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells

The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells

TGF-β-Based Therapies for Treating Ocular Surface Disorders

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors

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