更新于：2024-11-01

EGFR x JNK2

更新于：2024-11-01

基本信息

关联

项与 EGFR x JNK2 相关的药物

1,5-Diarylpyrazole derivatives-6c

靶点

EGFR x JNK2

作用机制

EGFR拮抗剂 [+1]

在研机构

Al-Azhar University

原研机构-

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 EGFR x JNK2 相关的临床结果

登录后查看更多信息

100 项与 EGFR x JNK2 相关的转化医学

登录后查看更多信息

0 项与 EGFR x JNK2 相关的专利（医药）

登录后查看更多信息

项与 EGFR x JNK2 相关的文献（医药）

2024-04-01·Bioorganic & Medicinal Chemistry Letters

Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation

Article

作者: Abdel-Aziz, Mohamed ; Konno, Hiroyuki ; Shoman, Mai E ; Narumi, Atsushi ; Soltan, Osama M ; Abdel-Aziz, Salah A ; Osawa, Keima ; Sh Shaykoon, Montaser

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC₅₀) values of 2.7-63 μM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC₅₀ of 2.0 and 0.9 μM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC₅₀ = 1.7 μM). Notably, 6c inhibited both kinases, with IC₅₀ values of 2.7 and 3.0 μM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.

2024-03-01·European Journal of Pharmacology

Epidermal growth factor receptor phosphorylation contributes to levobupivacaine-induced contraction in isolated rat aorta

Article

作者: Ahn, Seung Hyun ; Bae, Sung Il ; Lee, Soo Hee ; Ok, Seong-Ho ; Sohn, Ju-Tae ; Park, Kyeong-Eon ; Bae, Moonju ; Sim, Gyujin ; Hwang, Yeran

Vasoconstriction induced by levobupivacaine, a local anesthetic, is mediated by increased levels of calcium, tyrosine kinase, c-Jun NH₂-terminal kinase (JNK), and phospholipase D, which are associated with prolonged local anesthesia. Epidermal growth factor receptor (EGFR) phosphorylation is associated with vasoconstriction. However, its role in levobupivacaine-induced contractions remains unknown. We determined whether EGFR phosphorylation is associated with levobupivacaine-induced contractions in isolated rat thoracic aortas and identified the underlying cellular signaling pathways. The effects of various inhibitors and a calcium-free solution alone or in combination on levobupivacaine-induced contractions were then assessed. Furthermore, we examined the effects of various inhibitors on levobupivacaine-induced EGFR and JNK phosphorylation and calcium levels in vascular smooth muscle cells (VSMCs) of rat aortas. The EGFR tyrosine kinase inhibitor AG1478, matrix metalloproteinase (MMP) inhibitor GM6001, Src kinase inhibitors PP1 and PP2, and JNK inhibitor SP600125 attenuated levobupivacaine-induced contractions. Moreover, although the calcium-free solution abolished levobupivacaine-induced contractions, calcium reversed this inhibitory effect. The magnitude of the calcium-mediated reversal of abolished levobupivacaine-induced contractions was lower in the combination treatment with calcium-free solution and AG1478 than in the treatment with calcium-free solution alone. Levobupivacaine induced EGFR and JNK phosphorylation. However, AG1478, GM6001, and PP2 attenuated levobupivacaine-induced EGFR and JNK phosphorylation. Moreover, although levobupivacaine induced JNK phosphorylation in control siRNA-transfected VSMCs, EGFR siRNA inhibited levobupivacaine-induced JNK phosphorylation. Furthermore, AG1478 inhibited levobupivacaine-induced calcium increases in VSMCs. Collectively, these findings suggest that levobupivacaine-induced EGFR phosphorylation, which may occur via the Src kinase-MMP pathway, contributes to vasoconstriction via JNK phosphorylation and increased calcium levels.

2023-10-01·Molecular & Cellular Proteomics

A Multipathway Phosphopeptide Standard for Rapid Phosphoproteomics Assay Development

Article

作者: Neely, Benjamin A ; Hawke, David ; Herren, Anthony W ; Patel, Bhavin ; Leib, Ryan D ; Searle, Brian C ; Koller, Antonius ; Ren, Jian Min ; Lee, Kimberly A ; Nelson, Alissa J ; Stemmer, Paul M ; Chien, Allis ; Zhu, Yiying ; Patel, Purvi ; Kim Kim, Jenny

Recent advances in methodology have made phosphopeptide analysis a tractable problem for many proteomics researchers. There are now a wide variety of robust and accessible enrichment strategies to generate phosphoproteomes while free or inexpensive software tools for quantitation and site localization have simplified phosphoproteome analysis workflow tremendously. As a research group under the Association for Biomolecular Resource Facilities umbrella, the Proteomics Standards Research Group has worked to develop a multipathway phosphopeptide standard based on a mixture of heavy-labeled phosphopeptides designed to enable researchers to rapidly develop assays. This mixture contains 131 mass spectrometry vetted phosphopeptides specifically chosen to cover as many known biologically interesting phosphosites as possible from seven different signaling networks: AMPK signaling, death and apoptosis signaling, ErbB signaling, insulin/insulin-like growth factor-1 signaling, mTOR signaling, PI3K/AKT signaling, and stress (p38/SAPK/JNK) signaling. Here, we describe a characterization of this mixture spiked into a HeLa tryptic digest stimulated with both epidermal growth factor and insulin-like growth factor-1 to activate the MAPK and PI3K/AKT/mTOR pathways. We further demonstrate a comparison of phosphoproteomic profiling of HeLa performed independently in five labs using this phosphopeptide mixture with data-independent acquisition. Despite different experimental and instrumentation processes, we found that labs could produce reproducible, harmonized datasets by reporting measurements as ratios to the standard, while intensity measurements showed lower consistency between labs even after normalization. Our results suggest that widely available, biologically relevant phosphopeptide standards can act as a quantitative "yardstick" across laboratories and sample preparations enabling experimental designs larger than a single laboratory can perform. Raw data files are publicly available in the MassIVE dataset MSV000090564.