VTX-11e / Vertex, National Institutes of Health - LARVOL DELTA

Investigating the prognostic potential of PTPN11 gene in papillary thyroid carcinoma: A comprehensive study of bulk and single cell transcriptome. (PubMed, Medicine (Baltimore)) - "It exhibited strong binding affinities with VX-11e, irinotecan, and dactinomycin. Endothelial cells were identified as key cells; the occurrence of PTC reduced their quantity and affected the frequency/intensity of their interactions with mast cells. In conclusion, PTPN11 holds promise as a prognostic marker for PTC and is of great value for clinical management."

Biomarker • Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • DACT2 • MMP8 • NCAM1 • PTPN11

Explore the expression of mitochondria-related genes to construct prognostic risk model for ovarian cancer and validate it, so as to provide optimized treatment for ovarian cancer. (PubMed, Front Immunol) - "In terms of drug sensitivity, the high-risk group was more sensitive to vinblastine, Acetalax, VX-11e, and PD-0325901, while the low-risk group was more sensitive to Sabutoclax, SB-505124, cisplatin, and erlotinib. The prognostic risk model of ovarian cancer associated to mitochondrial genes built on the basis of public database better evaluated the prognosis of ovarian cancer patients and guided individual treatment."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Oncology • Ovarian Cancer • Solid Tumor • TMB

Clarifying new molecular subtyping and precise treatment of melanoma based on disulfidptosis-related lncRNA signature. (PubMed, Eur J Med Res) - "Subgroup C1 demonstrated better sensitivity to Zoledronate, UMI-77, Nilotinib, and Cytarabine. Subgroup C2 exhibited greater sensitivity to Ribociclib, XAV939, Topotecan, and Ruxolitinib. Subgroup C3 showed higher sensitivity to VX-11e, Ulixertinib, Trametinib, and Afatinib. This study revealed the immune microenvironment status and targeted drug sensitivity in melanoma patients with different risk scores and molecular subtypes, offering valuable guidance for clinical treatment and identifying significant DRL targets for future in-depth research."

Biomarker • Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Prognostic implication and immunotherapy response prediction of a novel ubiquitination-related gene signature in liver cancer. (PubMed, Aging (Albany NY)) - "In the high-risk group, erlotinib showed higher IC50 values compared to the low-risk group which exhibited higher IC50 values for VX-11e, AKT inhibitor VIII, AT-7519, BMS345541, Bortezomib, CP466722, FMK, and JNK-9L. The results of RT-qPCR revealed that the expression of four UEGs was higher in tumor tissue as compared to normal tissue. Based on the genes that were expressed differently and associated with ubiquitination-related tumor categorization, we have developed a pattern of four genes and a strong nomogram that can predict the prognosis of HCC, which could be useful in identifying and managing HCC."

Gene Signature • IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • MCM10 • TRIM54

Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2. (PubMed, Elife) - "An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site...The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors."

Journal • Oncology

Crosstalk between diacylglycerol kinase and protein kinase A in the regulation of airway smooth muscle cell proliferation. (PubMed, Respir Res) - "Our study provides insight into the molecular pathway (DAG-PKC/ERK-COXII-PGE-PKA) regulated by DGK in ASM cells and identifies DGK as a potential therapeutic target for mitigating ASM cell proliferation that contributes to airway remodeling in asthma."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK1

Diacylglycerol Kinase Inhibition Attenuates Airway Smooth Muscle Cell Proliferation Via Activation of Protein Kinase A (ATS 2023) - "In select experiments, ASM cells were pre-treated with BisI or Vx11e, PKC and ERK inhibitors, respectively, before treating cells with DGKI...The attenuation of ASM cell proliferation by DGK inhibition is perplexing and counterintuitive considering the activation of a pro-mitogenic ERK signal. In this regard, our study provides insight into the molecular pathways regulated by DGK in ASM cells, and identifies DGK as a potential therapeutic target for mitigating ASM cell proliferation, which contributes to airway remodeling in asthma."

Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • DGKI

Comprehensive Analysis of the Expression, Prognostic Value, and Immune Infiltration Activities of GABRD in Colon Adenocarcinoma. (PubMed, Mediators Inflamm) - "The IC50 of BI-2536, bleomycin, embelin, FR-180204, GW843682X, LY317615, NSC-207895, rTRAIL, and VX-11e was higher in the GABRD high-expression group. In conclusion, we have shown evidence that GABRD is a novel biomarker that is connected with immune cell infiltration in COAD and may be utilized to predict the prognosis of COAD patients."

Journal • Colon Cancer • Colorectal Adenocarcinoma • Gastrointestinal Cancer • Oncology • CD4 • CD8

Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors. (PubMed, J Biol Chem) - "Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRAS), colon cancer (HCT-116; KRAS), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Neuroblastoma • Oncology • Solid Tumor • KRAS • NRAS

PROGNOSTIC RELEVANCE AND ANTITUMOR OR IMMUNITY OF NSD3 OVEREXPRESSION IN THE BREAST CANCER (GBCC 2022) - "WHSC1L1 overexpression could play potential roles in the progression of breast cancer, and targeting WHSC1L1 could be a potential strategy for the treatment of breast cancer."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • CD8 • NSD3

VX-11e protects articular cartilage and subchondral bone in osteoarthritis by inhibiting the RIP1/RIP3/MLKL and MAPK signaling pathways. (PubMed, Bioorg Chem) - "VX-11e also inhibited RANKL-induced osteoclast differentiation by inhibiting the ERK/RSK signaling pathway, but not the NF-κB pathway. Overall, VX-11e inhibited the loss of articular cartilage and subchondral bone during OA by regulating the RIP1/RIP3/MLKL and MAPK signaling pathways."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • IL1B • RIPK1 • TRAP

The T-type Calcium Channel Cav3.1 in Y79 Retinoblastoma Cells is Regulated by the Epidermal Growth Factor Receptor via the MAPK Signaling Pathway. (PubMed, Curr Eye Res) - "At low concentrations (1 µM), Afatinib reduced the amplitude of Cav3.1 current density, whereas at a high concentration (10 µM), it completely abolished the voltage-gated calcium current. Our results show that inhibition of the MAPK pathway by a specific inhibitor VX-11e affected the Cav3.1 current in a dose-dependent manner...We also demonstrate that the specific inhibition of the Akt kinase (using MK-2206) had no effect on the Cav3.1 currents. Our study provides a functional relationship between the MAPK pathway and EGFR signaling and indicates that the MAPK signaling pathway mediates the control of Cav3.1 by EGFR in retinoblastoma."

Journal • Eye Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • EGFR

Blockage of Extracellular Signal-Regulated Kinase Exerts an Antitumor Effect via Regulating Energy Metabolism and Enhances the Efficacy of Autophagy Inhibitors by Regulating Transcription Factor EB Nuclear Translocation in Osteosarcoma. (PubMed, Front Cell Dev Biol) - "In this study, we identified an ERK inhibitor (ERKi; Vx-11e) with potential antitumor activities, which was reflected by the inhibition in the survival and proliferation of Osteosarcoma (OS) cells...Besides, we also found that the ERKi could regulate mitochondrial apoptosis through the ROS/mitochondria pathway and aerobic glycolysis in OS, which also increases the dependence of OS cells on autophagy to clear metabolites to a certain extent. These results may provide a reference for the clinically improved efficacy of ERKis in combination with autophagy inhibitors in the treatment of OS and indicate its potential as a therapeutic agent."

Clinical • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • TFEB