Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors

Hauguel, Camille; Ducellier, Sarah; Provot, Olivier; Ibrahim, Nada; Lamaa, Diana; Balcerowiak, Coline; Letribot, Boris; Nascimento, Megane; Blanchard, Vincent; Askenatzis, Laurie; Lévaique, Hélène; Bignon, Jérôme; Baschieri, Francesco; Bauvais, Cyril; Bollot, Guillaume; Renko, Dolor; Deroussent, Alain; Prost, Bastien; Laisne, Marie-Catherine; Michallet, Sophie; Lafanéchère, Laurence; Papot, Sébastien; Montagnac, Guillaume; Tran, Christine; Alami, Mouâd; Apcher, Sébastien; Hamzé, Abdallah

doi:10.1016/j.ejmech.2022.114573

Cited by 20 publications

(7 citation statements)

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“…Targeting different mechanisms simultaneously to increase the therapeutic efficacy of a drug can also be an intentionally implemented approach. For example, given the synergistic effect observed in combination therapies used in cancer treatment, involving tubulin-targeted drugs and other antitumor agents such as histone deacetylases inhibitors, DNA-damaging agents, or topoisomerase inhibitors, many efforts are now made to design of dual-target tubulin inhibitors [( Huang et al, 2019 ; Wu et al, 2020 ; Noha et al, 2021 ; Hauguel et al, 2022 ); and for a recent review see ( Shuai et al, 2021 )]. Compared to combination therapies such dual drugs may theoretically offer some advantages such as overcoming drug-resistance, superior treatment compliance, and lower risk of drug-drug interactions.…”

Section: All Roads Lead To Microtubules: Targeting Microtubules But U...mentioning

confidence: 99%

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

Lafanéchère

2022

Front. Pharmacol.

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Compounds targeting microtubules are widely used in cancer therapy with a proven efficacy. However, because they also target non-cancerous cells, their administration leads to numerous adverse effects. With the advancement of knowledge on the structure of tubulin, the regulation of microtubule dynamics and their deregulation in pathological processes, new therapeutic strategies are emerging, both for the treatment of cancer and for other diseases, such as neuronal or even heart diseases and parasite infections. In addition, a better understanding of the mechanism of action of well-known drugs such as colchicine or certain kinase inhibitors contributes to the development of these new therapeutic approaches. Nowadays, chemists and biologists are working jointly to select drugs which target the microtubule cytoskeleton and have improved properties. On the basis of a few examples this review attempts to depict the panorama of these recent advances.

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Section: All Roads Lead To Microtubules: Targeting Microtubules But U...mentioning

confidence: 99%

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

Lafanéchère

2022

Front. Pharmacol.

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“…Regarding HDAC proteins, HDAC6 has shown an increased activity involved in several pathologies, 7 including NSCLC and is linked to bad prognosis. 29 Here, we used a small molecule, QAPHA, already described as a tubulin polymerization and HDACs inhibitor, 13 that is, able to bind and inhibit HDAC6 activity in TC-1 cells in vitro. This inhibition is correlated with the reactivation of cell death pathways through upregulation of HSP90, cytochrome C and caspases expression.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, multitargeted molecules, iethat is, when one molecule can interact and thus inhibit several different targets at the same time, are more likely to be used, which may offer advantages such as a reduced risk of interactions between the different treatments as well as improved efficacy. We have recently reported that a HDACi can also be a specific tubulin polymerization inhibitor 13 and showed complete tumor regression in MCA205 fibrosarcoma mouse model.…”

Section: What This Study Addsmentioning

confidence: 99%

Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

Ducellier,

Demeules,

Letribot

et al. 2024

J Immunother Cancer

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BackgroundDespite the current therapeutic treatments including surgery, chemotherapy, radiotherapy and more recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered that a molecule called QAPHA ((E)−3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)−2-methoxyphenyl)-N-hydroxyacrylamide) has a dual function as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the immune response to lung cancer.MethodsTo elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterized by flow cytometry.ResultsIn this study, we first showed that QAPHA effectively inhibited histone deacetylase 6, leading to upregulation of HSP90, cytochrome C and caspases, as revealed by proteomic analysis. We confirmed that QAPHA induces immunogenic cell death (ICD) by expressing calreticulin at cell surface in vitro and demonstrated its efficacy as a vaccine in vivo. Remarkably, even at a low concentration (0.5 mg/kg), QAPHA achieved complete tumor regression in approximately 60% of mice treated intratumorally, establishing a long-lasting anticancer immune response. Additionally, QAPHA treatment promoted the infiltration of M1-polarized macrophages in treated mice, indicating the induction of a pro-inflammatory environment within the tumor. Very interestingly, our findings also revealed that QAPHA upregulated major histocompatibility complex class II (MHC-II) expression on TC-1 tumor cells both in vitro and in vivo, facilitating the recruitment of cytotoxic CD4+T cells (CD4+CTL) expressing CD4+, NKG2D+, CRTAM+, and Perforin+. Finally, we showed that tumor regression strongly correlates to MHC-II expression level on tumor cell and CD4+CTL infiltrate.ConclusionCollectively, our findings shed light on the discovery of a new multitarget inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate in enhancing a specific CD4+cytotoxic T cell-mediated antitumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising agent for cancer treatment.

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“…The anti-proliferative and anti-tubulin activities positively correlated with the effects observed on cell-cycle progression and HDAC8 inhibition. In addition, metabolic studies proved the enhanced stability of this second-generation dual TP/HDAC8is [ 180 ].…”

Section: Multi-target Pharmacological Tools Acting On Hdac8mentioning

confidence: 99%

“… Representation of reported dual TP/HDAC8is, MMP2/HDAC8is and BRPF1/HDAC8is [ 179 , 180 , 184 , 185 ]. …”

Section: Multi-target Pharmacological Tools Acting On Hdac8mentioning

confidence: 99%

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Fontana

Cursaro

Carullo

et al. 2022

IJMS

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Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.

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Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors

Cited by 20 publications

References 62 publications

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

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