The ALK inhibitors, alectinib and ceritinib, induce ALK‐independent and STAT3‐dependent glioblastoma cell death

Kawauchi, Daisuke; Takahashi, Manabu; Satomi, Kaishi; Yamamuro, Shun; Kobayashi, Tatsuya; Uchida, Eita; Honda‐Kitahara, Mai; Narita, Yoshitaka; Iwadate, Yasuo; Ichimura, Koichi; Tomiyama, Arata

doi:10.1111/cas.14885

Cited by 7 publications

(6 citation statements)

References 40 publications

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“…On similar lines, CDK2 promotes cancer progression and resistance to radiotherapy (Wang et al, 2016). Alectinib and ceritinib, ALK inhibitors, have demonstrated cell‐killing effects in glioblastoma (Kawauchi et al, 2021). In summary, all three targets have been implicated in GBM pathology and developing novel, preferentially selective inhibitors of these kinases makes perfect therapeutic sense.…”

Section: Resultsmentioning

confidence: 99%

“…As seen from Table 4, hits F 2 and F 7 were selected for further computational screening for potential molecular targets using SwissTargetPrediction (Gfeller et al, 2013) demonstrated cell-killing effects in glioblastoma (Kawauchi et al, 2021). In summary, all three targets have been implicated in GBM pathology and developing novel, preferentially selective inhibitors of these kinases makes perfect therapeutic sense.…”

Section: Biological Evaluationmentioning

confidence: 99%

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Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

Khairnar

Sonawane

Cheke

et al. 2023

Drug Development Research

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Glioblastoma multiforme (GBM) is a highly‐aggressive, dreadful disease with poor prognosis and disappointing clinical success. There is an unmet medical need of molecularly‐targeted therapeutics for GBM treatment. In the present work, a series of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines was designed, synthesized, purified, characterized, and evaluated for cytotoxicity against glioblastoma cell line U87‐MG. The design process (virtual library enumeration around the core, physicochemical and molecular property prediction/calculation of the designs, filtering the undesirable ones, and the diversity analyses of the lead‐like designs), was carefully curated so as to obtain a set of structurally‐diverse, novel molecules (total 20), with a particular focus on the relatively unexplored core structure, 6,7‐dihydro‐5H‐cyclopenta[d]pyrimidine. The preliminary screening was done using MTT assay at 10 and 100 μM concentrations of the title compounds F1−F20 and positive control cisplatin, which yielded six hits (% inhibition at 10 μM: ~50%)—F2, F3, F5, F7, F15, and F20, which were taken up for IC50 determination. The top hits F2 and F7 (IC50 < 10 μM) were further used for computational studies such as target prediction, followed by their molecular docking in the binding sites of the top‐3 predicted targets (epidermal growth factor receptor kinase domain, cyclin‐dependent kinase 2 [CDK2]) /cyclin E, and anaplastic lymphoma kinase [ALK]). The docking pose analyses revealed interesting trends. The relatively planar core structure, presence of favorable hinge‐binding substructures, basic groups, all added up, and culminated in appreciable cytotoxicity against GBM cell line.

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Section: Resultsmentioning

confidence: 99%

Section: Biological Evaluationmentioning

confidence: 99%

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

Khairnar

Sonawane

Cheke

et al. 2023

Drug Development Research

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“…type="uri"> receptor , the insulin receptor, and the serine/threonine protein kinase STK22D (TSSK1). 59 The compound had been found to display growth inhibition and cellular toxicity of tumor cells, which may be dependent on its strong inhibition of ALK and other kinases; 72 ceritinib’s cytotoxic mechanism of action may, in fact, be due to its polypharmacology, 73 74 to which CD39 inhibition might additionally contribute.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy

Schäkel

Mirza

Winzer

et al. 2022

J Immunother Cancer

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BackgroundAn important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A2A and A2B receptors on immune cells constituting one of the strongest immunosuppressive mediators. In addition, extracellular adenosine promotes angiogenesis, tumor cell proliferation, and metastasis. Cancer cells upregulate ectonucleotidases, most importantly CD39 and CD73, which catalyze the hydrolysis of extracellular ATP to AMP (CD39) and further to adenosine (CD73). Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small molecule inhibitors for CD39 are not available. Our aim was to identify drug-like CD39 inhibitors and evaluate them in vitro.MethodsWe pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations, and on human immune and cancer cells.ResultsThe tyrosine kinase inhibitor ceritinib, a potent anticancer drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. The drug displays a non-competitive, allosteric mechanism of CD39 inhibition exhibiting potency in the low micromolar range, which is independent of substrate (ATP) concentration. We could show that ceritinib inhibits ATP dephosphorylation in peripheral blood mononuclear cells in a dose-dependent manner, resulting in a significant increase in ATP concentrations and preventing adenosine formation from ATP. Importantly, ceritinib (1–10 µM) substantially inhibited ATP hydrolysis in triple negative breast cancer and melanoma cells with high native expression of CD39.ConclusionsCD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.

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“…Kawauchi et al [44] demonstrated the anticancer activity of alectinib and ceritinib against U87MG, LN229, and GSC23 GBM cell lines. ALK inhibitors effectively induced GBM cell death and inhibited STAT3, causing caspase-dependent/independent cell death when administered alone.…”

Section: Crizotinib Alectinib and Ceritinibmentioning

confidence: 99%

“…AXL phosphorylation leads to PI3K and AKT activation. The Gas6/AXL/PI3K/Akt axis protects cells from apoptosis by S6K activation and BCL-2 phosphorylation [44]. AXL is widely expressed in GBM, and its biologically active form Phospho-AXL (P-AXL) is associated with poor prognosis [48].…”

Section: Axl Inhibitorsmentioning

confidence: 99%

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

Frumento,

Grossi,

Falesiedi

et al. 2024

IJMS

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In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15–16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials.

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The ALK inhibitors, alectinib and ceritinib, induce ALK‐independent and STAT3‐dependent glioblastoma cell death

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 7 publications

References 40 publications

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

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