Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy

Zhang, Lingzhi; Ju, Qiurong; Sun, Jinjin; Huang, Lei; Wu, Shiqi; Wang, Shuping; Li, Yin; Guan, Zhe; Zhu, Qihua; Xu, Yungen

doi:10.3390/molecules25235693

Cited by 6 publications

(7 citation statements)

References 22 publications

(23 reference statements)

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“…16). 51 Compounds 73-75 were foundd to be dual inhibitors of ERK2 and PI3K-a. Compound 74, a potent and very effective ERK and PI3K dual inhibitor, was discovered during preliminary SAR study.…”

Section: Extracellular Regulated Protein Kinases (Erk)mentioning

confidence: 99%

“…The combined inhibition of the MAPK and PI3K signalling pathways has been identied as a viable cancer therapy that effectively overcomes the drug resistance of MAPK signalling pathway inhibitors. 51 Zhang et al reported the scaffold-hopping synthesis of ERK/ PI3K dual inhibitors by replacing 1H-pyrazolo [3,4- 1% inhibitory activity at the concentration of 1 mM on ERK2 and PI3Ka respectively (Fig. 16).…”

Section: Extracellular Regulated Protein Kinases (Erk)mentioning

confidence: 99%

“…The combined inhibition of the MAPK and PI3K signalling pathways has been identified as a viable cancer therapy that effectively overcomes the drug resistance of MAPK signalling pathway inhibitors. 51 …”

Section: Molecular Targets Of Pyrido[23- D ]Pyrimi...mentioning

confidence: 99%

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Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

et al. 2023

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Section: Extracellular Regulated Protein Kinases (Erk)mentioning

confidence: 99%

Section: Extracellular Regulated Protein Kinases (Erk)mentioning

confidence: 99%

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Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

et al. 2023

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“…Studies of cross-talks between PI3K signaling and other pathways are thought will guide future combination strategies of using clinically relevant inhibitors in various tumor types ( 72 , 73 ). Overall, the available evidence suggests that drug resistance (intrinsic or acquired) to such targeted therapies results at least in part from negative feedback interactions between these kinases, combined with tumor heterogeneity, cellular state, mutational background, etc.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

et al. 2023

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There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients’ lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling – selumetinib, trametinib, and SCH772984 – increased AKT phosphorylation, and conversely, inhibitors of AKT – capivasertib, idelalisib, and AKT inhibitor VIII – increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy.

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“…1H-Pyrazolo [3,4-d]pyrimidine is an important structural fragment present in naturally occurring nucleosides (Formycin A and Formycin B), which have significant antitumor activity [1,2]. Additionally, 1H-pyrazolo [3,4-d]pyrimidines exhibit various biological activities, including antiviral and analgesic activity, treatment of male erectile dysfunction and hyperuricemia, prevention of gout, and many others [1, 3,4]. Functionally substituted 1H-pyrazolo [3,4-d]pyrimidines showed good antibacterial and antiproliferative activity [5].…”

Section: Introductionmentioning

confidence: 99%

4-Chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Ogurtsov

Ракитин

2021

Molbank

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A novel 4-chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was prepared by a rational and short two-step synthesis from commercially available ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate via 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one. The structure of the synthesized compounds was established by elemental analysis, high-resolution mass-spectrometry, 1H, 13C-NMR and IR spectroscopy and mass-spectrometry. 4-Chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine is a convenient intermediate for various disubstituted 1-methyl-1H-pyrazolo[3,4-d]pyrimidines, which may be of interest as substances with useful pharmacological properties.

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Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy

Cited by 6 publications

References 22 publications

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

4-Chloro-6-(chloromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

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