ArticleOncotarget2012
Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2.
Article in Oncotarget, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 59 citations in OpenAlex.
- Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma.The Journal of dermatology · 2018Trial
- Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review).International journal of oncology · 2026Review
- Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.bioRxiv : the preprint server for biology · 2026Article
- Mutant and Wild-Type RAS Cross-talk and Stoichiometric Deficiencies Are Determinants of Sensitivity to Targeted Therapies in KRASG12R Pancreatic Ductal Adenocarcinoma.Cancer research · 2026Article
- Multi-omic profiling defines three distinct molecular subtypes of urothelial carcinoma with implications for precision therapy.Clinical and translational medicine · 2026Article
- RAF isoform selectivity of MEK inhibitors and rational design of a covalent ARAF-MEK inhibitor.bioRxiv : the preprint server for biology · 2025Article
- Mechanistic modeling of cell viability assays with in silico lineage tracing.PLoS computational biology · 2025Article
- Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia.Molecular cancer · 2024Article
- Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.Nature communications · 2024Article
- Live-cell target engagement of allosteric MEKi on MEK-RAF/KSR-14-3-3 complexes.Nature chemical biology · 2024Article
- Article
- DeepFLR facilitates false localization rate control in phosphoproteomics.Nature communications · 2023Article
- Phenotypic drug discovery: recent successes, lessons learned and new directions.Nature reviews. Drug discovery · 2022Review
- Article
- Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Article
- Establishment and characterization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma.Scientific reports · 2020Article
- Myeloid-Derived Suppressor Cells as a Regulator of Immunity in Organ Transplantation.International journal of molecular sciences · 2018Review
- Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma.Neuro-oncology · 2017Article
- Overcoming resistance to HER2 inhibitors through state-specific kinase binding.Nature chemical biology · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A small molecule compound, JTP-74057/GSK1120212/trametinib, had been discovered as a very potent antiproliferative agent able to induce the accumulation of CDK inhibitor p15INK4b. To conduct its drug development rationally as an anticancer agent, molecular targets of this compound were identified as MEK1/2 using compound-affinity chromatography. It was shown that JTP-74057 directly bound to MEK1 and MEK2 and allosterically inhibited their kinase activities, and that its inhibitory characteristics were similar to those of the known and different chemotype of MEK inhibitors PD0325901 and U0126. It was further shown that JTP-74057 induced rapid and sustained dephosphorylation of phosphorylated MEK in HT-29 colon and other cancer cell lines, while this decrease in phosphorylated MEK was not observed in PD0325901-treated cancer cells. Physicochemical analyses revealed that JTP-74057 preferentially binds to unphosphorylated MEK (u-MEK) in unique characteristics of both high affinity based on extremely low dissociation rates and ability stabilizing u-MEK with high thermal shift, which were markedly different from PD0325901. These findings indicate that JTP-74057 is a novel MEK inhibitor able to sustain MEK to be an unphosphorylated form resulting in pronounced suppression of the downstream signaling pathways involved in cellular proliferation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.