Design, synthesis and antitumor evaluation of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives as potential c-Met inhibitors

Luo, Guolin; Ma, Yu; Liang, Xintong; Xie, Guoquan; Luo, Yingqi; Zha, Dailong; Wang, Sheng; Yu, Lei; Zheng, Xuehua; Wu, Wenhao; Zhang, Chao

doi:10.1016/j.bioorg.2020.104356

Cited by 16 publications

(6 citation statements)

References 29 publications

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“…Here, siRNA-mediated c-MET downregulation or PHA-665752-mediated c-MET tyrosine kinase activity inhibition prevented HGF-dependent activation of the PI3K/AKT and MAPK pathways and resensitized cells to cetuximab-induced growth-inhibitory effects. Many c-MET-targeting therapeutics, including TKIs, mAbs, and molecular decoys, are currently undergoing clinical development [62][63][64][65]. The efficacy and safety of combined receptor tyrosine kinase (RTK) therapy should be evaluated in vivo to overcome EGFR TKI resistance in the future.…”

Section: Discussionmentioning

confidence: 99%

LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways

Hong¹,

Zhang²,

Wei³

et al. 2022

J. Cancer

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Background: Cetuximab is one of the most widely used monoclonal antibodies to treat patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Unfortunately, cetuximab resistance often occurs during targeted therapy. However, the underlying epigenetic mechanisms remain unclear. Our previous study demonstrated that the exosomal transfer of urothelial carcinoma-associated 1 (UCA1) confers cetuximab resistance to CRC cells. The goal of this study was to elucidate the detailed role of UCA1 in cetuximab resistance in CRC and the underlying molecular mechanism. Methods: In vitro and in vivo functional studies were performed to assess the role of UCA1 in cetuximab resistance in CRC cell lines and xenograft models. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to examine UCA1 localization and expression. Bioinformatics analysis was performed to predict the potential mechanism of UCA1, which was further validated by the dual-luciferase reporter assay and the RNA immunoprecipitation (RIP) assay. Cells treated with indicators were subjected to Cell Counting Kit-8 (CCK-8) and western blotting to investigate the role of hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition (c-MET) signalling in UCA1-mediated cetuximab resistance. Results: We showed that UCA1 decreased CRC cell sensitivity to cetuximab by suppressing apoptosis. Mechanistic studies revealed that UCA1 promoted cetuximab resistance by competitively binding miR-495 to facilitate HGF and c-MET expression in CRC cells. Moreover, HGF was shown to attenuate the cetuximab-induced inhibition of cell proliferation by activating the HGF/c-MET pathway in CRC cells. Conclusion:We provide the first evidence of a UCA1-miR-495-HGF/c-MET regulatory network involved in cetuximab resistance in CRC. Therefore, UCA1 has potential as a predictor and therapeutic target for cetuximab resistance.

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Section: Discussionmentioning

confidence: 99%

LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways

Hong¹,

Zhang²,

Wei³

et al. 2022

J. Cancer

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“…In this context there is a great demand for improving cancer chemotherapy, and the researcher’s efforts towards this aim revealed the development of novel multifunctional anticancer drugs that combine two or more pharmacophores in a single molecule as the future of chemotherapy [ 6 ]. In this regard, many pharmacophores combinations based on inorganic [ 7 , 8 , 9 ] and/or organic compounds [ 10 , 11 , 12 , 13 , 14 , 15 ] are currently investigated. Among the organic pharmacophores, nitrogen-containing heterocycles proved to have the most promising anticancer activity, being studied in various combinations [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of PEGylated and TEGylated Phenothiazine Derivatives: Structure–Activity Relationship

Cibotaru¹,

Sandu²,

Nicolescu³

et al. 2023

IJMS

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The paper aims to investigate the antitumor activity of a series of phenothiazine derivatives in order to establish a structure–antitumor activity relationship. To this end, PEGylated and TEGylated phenothiazine have been functionalized with formyl units and further with sulfonamide units via dynamic imine bonds. Their antitumor activity was monitored in vitro against seven human tumors cell lines and a mouse one compared to a human normal cell line by MTS assay. In order to find the potential influence of different building blocks on antitumor activity, the antioxidant activity, the ability to inhibit farnesyltransferase and the capacity to bind amino acids relevant for tumor cell growth were investigated as well. It was established that different building blocks conferred different functionalities, inducing specific antitumor activity against the tumor cells.

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“…Unit B is a linker bridge that could be a linear chain or a heterocyclic ring and should possess hydrogen-bond donors or acceptors. On the other hand, unit C exhibits a high degree of structural diversity, such as pyridine or its analogues attached to a different substituted phenyl moiety, resulting in the creation of hydrogen bonds and p-p stacking interactions with the backbone of the c-Met enzyme [23][24][25] (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

New pyrazolopyridine and pyrazolothiazole-based compounds as anti-proliferative agents targeting c-Met kinase inhibition: design, synthesis, biological evaluation, and computational studies

et al. 2023

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Design, synthesis and antitumor evaluation of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives as potential c-Met inhibitors

Cited by 16 publications

References 29 publications

LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways

LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways

Antitumor Activity of PEGylated and TEGylated Phenothiazine Derivatives: Structure–Activity Relationship

New pyrazolopyridine and pyrazolothiazole-based compounds as anti-proliferative agents targeting c-Met kinase inhibition: design, synthesis, biological evaluation, and computational studies

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