Synthesis and anti-tumor activity of imidazopyrazines as TAK1 inhibitors

Kang, Seok Jong; Lee, Jung Wuk; Chung, Shin; Jang, Sun Young; Choi, Jaeyul; Suh, Kwee Hyun; Kim, Young Hoon; Ham, Young Jin; Min, Kyung Hoon

doi:10.1016/j.ejmech.2018.12.025

Cited by 11 publications

(3 citation statements)

References 27 publications

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“…Beyond the therapeutic proposals based on the TGFβ canonical pathways, two of the studies included in this review proposed TAK1 as a drug target in pancreatic and breast cancer treatment [101]. A derivate from imidazopyrazine presented a significant in vivo antitumor effect in mice subjected to xenotransplantation with human mutant KRAS-dependent CRC cells [101]. Additionally, the TAK1 inactivation by the inhibitor 5Z7 (5Z-7-oxozeaenol) improved the efficiency of the treatment with Taxol (paclitaxel) in ovarian cancer cells.…”

Section: Small Molecule Inhibitors (Smi)mentioning

confidence: 99%

Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

Gómez-Gil¹

2021

Cancers

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Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFβ, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFβ, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFβ and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFβ synthesis, to molecules that block the interaction between TGFβ and its signaling receptors, together with inhibitors of the TGFβ signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.

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Section: Small Molecule Inhibitors (Smi)mentioning

confidence: 99%

Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

Gómez-Gil¹

2021

Cancers

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“…On the other hand, urea derivatives are widely applied in medicinal synthesis due to their various biological activities, such as anti-inflammatory ( Drexel et al, 2019 ), antitumor activities ( Kang et al, 2019 ; Kilic-Kurta et al, 2020 ), and antimicrobial ( Lafzi et al, 2021 ). Recent reports showed that urea derivatives could inhibit cell signaling transduction, such as RAS-RAFMEK-ERK signaling pathway and PI3K/Akt/mTOR pathway ( Li et al, 2019 ), and inhibit protein activity, such as mTORC1 and mTORC2 ( Gao et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of Menthone-Derived Pyrimidine-Urea Compounds as Potential PI3K/Akt/mTOR Signaling Pathway Inhibitor

et al. 2022

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A series of novel menthone derivatives bearing pyrimidine and urea moieties was designed and synthesized to explore more potent natural product-derived antitumor agents. The structures of the target compounds were confirmed by FTIR, NMR, and HRMS. The in vitro antitumor activity was tested by standard methyl thiazolytetrazolium assay and showed that 4i, 4g, 4s, and 4m are the best compounds with IC50 values of 6.04 ± 0.62µM, 3.21 ± 0.67µM, 19.09 ± 0.49µM, and 18.68 ± 1.53µM, against Hela, MGC-803, MCF-7, and A549, respectively. The results of the preliminary action mechanism studies showed that compound 4i, the representative compound, could induce cell apoptosis in Hela cells in a dose-dependent manner and might arrest the cell cycle in the G2/M phase. Furthermore, the results of network pharmacology prediction and Western blot experiments indicated that compound 4i might inhibit Hela cells through inhibit PI3K/Akt/mTOR signaling pathway. The binding modes and the binding sites interactions between compound 4i and the target proteins were predicted preliminarily by the molecular docking method.

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“…Over the past years, benzimidazole derivatives have been widely studied for their antimalarial 34 , anticancer 35 , antiprotozoal 36 , anti-inflammatory, and analgesic 37 activities. On the other hand, imidazo [1,2-a]pyrazine is also reported as cyclic nucleotide phosphodiesterase inhibitor 38 , anticancer 39 , anti-inflammatory 40 , antioxidant 41 , antimicrobial 42 , antiviral 43 , and antimalarial agents 44 . Thus, the designing of benzimidazole-imidazo[1,2-a] pyrazine hybrid ring system has been taken that provides new compounds related to various biological activities of benzimidazole and imidazopyrazine, in the hope that new anti-tumor agents might be discovered.…”

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confidence: 99%

Synthesis, cytotoxicity, pharmacokinetic profile, binding with DNA and BSA of new imidazo[1,2-a]pyrazine-benzo[d]imidazol-5-yl hybrids

Singh

Luxami

Paul

2020

Sci Rep

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Novel derivatives possessing imidazo[1,2-a]pyrazine and 1H-benzo[d]imidazole scaffolds were synthesized using Suzuki-Miyaura cross-coupling reactions. In vitro anticancer activities against NCI-60 cancer cell panels were tested at 10 µM concentration. The best results were obtained from substitution of two 1-cyclohexyl-1H-benzo[d]imidazole groups present at C-6 and C-8 positions of imidazo[1,2-a] pyrazine (31). Compound 31 was found to be cytotoxic against 51 cell lines and cytostatic against 8 cell lines with broad range of growth inhibitions (−98.48 to 98.86%). GI 50 value of compound 31 was found in the range of 0.80-2.87 µM for 59 human cancer cell lines at five-dose concentration levels. DNA binding study of potent compound 31 was suggested that this compound was intercalated into DNA base pairs with binding constant of 1.25 × 10 4 M −1. Compound 31 showed effective binding with bovine serum albumin (BSA) and presented binding constant value of 3.79 ×10 4 M-1. Pharmacokinetic studies revealed that all compounds are following Lipinski's rule of five and expected to be orally active. Cancer is one of the major reasons for death globally. Millions of people suffer or die from cancer each year, and there is no particular good medication available at present 1. Cancer has significant economic impact, which is increasing gradually. In the field of cancer treatment, chemists have great challenges to discover new and efficient compounds with strong and broad-spectrum anticancer activity. Heterocyclic ring systems play significant role in the discovery of novel bioactive substances due to their minimal side effects and effective at small doses. Heterocyclic moieties are widely present in various natural bioactive compounds 2. Undesirable side effects, toxicity, drug resistance, and low bioavailability are some of the major known problems for currently available anticancer agents 3. Therefore, there is an urgent need for the discovery of more efficient and selective anticancer agent. The biological potential of these heterocycles towards cancer cells has been stated with diverse mechanism of action. Most of the anticancer candidates bind with DNA double-strand and interfere with replication and transcription, thus, interrupt DNA function and alter the cell division. These candidates show interaction between adjacent base pairs or bind with grooves of DNA. These candidates share similar structural features, for example, the presence of planarity in structure, which can help the molecule to bind with DNA through insertion between base-pairs. The basic chain connected with these heterocyclic moieties plays a significant role in the selectivity and affinity 4. Due to their high affinity, the discovery of novel DNA intercalator for cancer therapy is a crucial goal in the medicinal chemistry. These intercalators comprise anthracyclines 5,6 (e.g. doxorubicin and mitoxantrone), ellipticine 7 and acridine derivatives (e.g. amsacrine) 8 , used in the cancer therapy of acute leukemia, breast, and ovarian cancers. On account of r...

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Synthesis and anti-tumor activity of imidazopyrazines as TAK1 inhibitors

Cited by 11 publications

References 27 publications

Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

Synthesis and Antitumor Evaluation of Menthone-Derived Pyrimidine-Urea Compounds as Potential PI3K/Akt/mTOR Signaling Pathway Inhibitor

Synthesis, cytotoxicity, pharmacokinetic profile, binding with DNA and BSA of new imidazo[1,2-a]pyrazine-benzo[d]imidazol-5-yl hybrids

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