What drugs are MEK inhibitors?

MEK inhibitors The MEK gene works together with the BRAF gene, so drugs that block MEK proteins can also help treat melanomas with BRAF gene changes. MEK inhibitors include trametinib (Mekinist), cobimetinib (Cotellic), and binimetinib (Mektovi) .

What are the FDA approved MEK inhibitors?

To date, four MEK inhibitors have been approved by the United States Food and Drug Administration (FDA), including trametinib, binimetinib, selumetinib, and cobimetinib [19–22].

What is the success rate of MEK inhibitors?

Approximately 50% of patients with melanoma harbor a BRAF mutation and are eligible for targeted therapy with BRAF/MEK inhibitors (BRAFi/MEKi). Despite a response rate of nearly 70% , more than half of the patients will experience disease progression within a year due to tumor resistance.

What are the side effects of MEK inhibitors?

The adverse events included diarrhea, vomiting, stomatitis, and dry skin with increased neutropenic effects above what would be expected for docetaxel alone. Further study with larger cohorts will be needed to determine if specific KRAS mutations can further predict for response to MEK inhibition.

What is the most potent MEK inhibitor?

Compared with other three FDA-approved MEK inhibitors, tunlametinib showed much more potent both in vitro and in vivo. The phosphorylation of ERK, biomarker of MEK inhibition, was evidently inhibited after tunlametinib was administered to cells in vitro or xenograft model in vivo.

Is MEK a tumor suppressor?

MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1 .

Does trametinib cause weight gain?

An increase in weight-for-age percentile ≥5% was seen in 60% of patients receiving selumetinib and 56% on trametinib .

What is the first approved MEK inhibitor?

Trametinib was the first MEK inhibitor to be approved by the FDA for the treatment of metastatic or unresectable melanoma in May 2013 .

What are MEK inhibitors for MAPK?

Mitogen-activated protein kinases inhibitors MEK inhibitors have clinical activity in melanoma patients who harbor that V600 mutation and are mostly used in combination with BRAF inhibitors. Trametinib and cobimetinib are potent, highly specific inhibitors of MEK1/MEK2.

What is the full form of MEK inhibitors?

MEK: mitogen-activated protein kinase kinase .

What is MEK in pharmacology?

MEK is a key enzyme in the Ras/Raf/MEK/ERK signal transduction pathway and mediates cellular responses to different growth signals . This pathway is frequently deregulated in cancer, which makes these enzymes a candiate target for pharmacological antineoplastic treatment.

Small-molecule High-throughput Screening Identifies an MEK Inhibitor PD198306 that Enhances Sorafenib Efficacy via MCL-1 and BIM in Hepatocellular Carcinoma Cells (2024)

Abstract

Background: Sorafenib is the most widely used systematic therapy drug for treating unresectableHepatocellular Carcinoma (HCC) but showed dissatisfactory efficacy in clinical applications.

Objective: We conducted a combinational quantitative small-molecule high-throughput screening(qHTS) to identify potential candidates to enhance the treatment effectiveness of sorafenib.

Methods: First, using a Hep3B human HCC cell line, 7051 approved drugs and bioactive compoundswere screened, then the primary hits were tested with/without 0.5 μM sorafenib respectively,the compound has the half maximal Inhibitory Concentration (IC50) shift value greater than 1.5 wasthought to have the synergistic effect with sorafenib. Furthermore, the MEK inhibitor PD198306was selected for the further mechanistic study.

Results: 12 effective compounds were identified, including kinase inhibitors targeting MEK,AURKB, CAMK, ROCK2, BRAF, PI3K, AKT and EGFR, and a μ-opioid receptor agonist and a Ltypecalcium channel blocker. The mechanistic research of the combination of sorafenib plusPD198306 showed that the two compounds synergistically inhibited MEK-ERK and mTORC1-4EBP1 and induced apoptosis in HCC cells, which can be attributed to the transcriptional and posttranslationalregulation of MCL-1 and BIM.

Conclusion: Small-molecule qHTS identifies MEK inhibitor PD1938306 as a potent sorafenib enhancer,together with several novel combination strategies that are valuable for further studies.

Keywords: Small-molecule high-throughput screening, hepatocellular carcinoma, sorafenib, MEK inhibitor, angiogenesis, calcium channel blocker.

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Combinatorial Chemistry & High Throughput Screening

Title:Small-molecule High-throughput Screening Identifies an MEK InhibitorPD198306 that Enhances Sorafenib Efficacy via MCL-1 and BIM inHepatocellular Carcinoma Cells

Volume: 26 Issue: 7

Author(s): Junjie Hong, Wei Zheng and Xiujun Cai*

Affiliation:

Department of General Surgery, Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Sir RunRun Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310016, China

Keywords: Small-molecule high-throughput screening, hepatocellular carcinoma, sorafenib, MEK inhibitor, angiogenesis, calcium channel blocker.

Abstract:

Background: Sorafenib is the most widely used systematic therapy drug for treating unresectableHepatocellular Carcinoma (HCC) but showed dissatisfactory efficacy in clinical applications.

Objective: We conducted a combinational quantitative small-molecule high-throughput screening(qHTS) to identify potential candidates to enhance the treatment effectiveness of sorafenib.

Conclusion: Small-molecule qHTS identifies MEK inhibitor PD1938306 as a potent sorafenib enhancer,together with several novel combination strategies that are valuable for further studies.

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Hong Junjie, Zheng Wei and Cai Xiujun*, Small-molecule High-throughput Screening Identifies an MEK InhibitorPD198306 that Enhances Sorafenib Efficacy via MCL-1 and BIM inHepatocellular Carcinoma Cells, Combinatorial Chemistry & High Throughput Screening 2023; 26 (7) . https://dx-doi-org-s.webvpn.ccmu.edu.cn/10.2174/1386207325666220830145026

DOI https://dx-doi-org-s.webvpn.ccmu.edu.cn/10.2174/1386207325666220830145026	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402