YAP1 x mTOR x MEK1 x EGFR

Last update 01 Nov 2024

Basic Info

Related Targets

YAP1mTORMEK1[+1]

Drugs associated with YAP1 x mTOR x MEK1 x EGFR

NLOC-015A

Target

EGFR x MEK1 x YAP1 x mTOR

Mechanism

EGFR antagonists [+3]

Active Org.

Taipei Medical University

Originator Org.

Taipei Medical University

Active Indication

Non-Small Cell Lung Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with YAP1 x mTOR x MEK1 x EGFR

100 Translational Medicine associated with YAP1 x mTOR x MEK1 x EGFR

0 Patents (Medical) associated with YAP1 x mTOR x MEK1 x EGFR

Literatures (Medical) associated with YAP1 x mTOR x MEK1 x EGFR

Frontiers in Immunology

Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule

Article

Author: Huang, Hsu-Shan ; Wu, Alexander T H ; Lawal, Bashir

Lung cancer poses a serious threat to human health and has recently been tagged the most common malignant disease with the highest incidence and mortality rate. Although epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, patients often develop resistance to these drugs. There is therefore a need to identify new drug candidates with multitarget potential for treating NSCLC. We hereby provide preclinical evidence of the therapeutic efficacy of NLOC-015A a multitarget small-molecule inhibitor of EGFR/mitogen-activated protein (MAP) kinase kinase 1 (MAP2K1)/mammalian target of rapamycin (mTOR)/yes-associated protein 1 (YAP1) for the treatment NSCLC. Our multi-omics analysis of clinical data from cohorts of NSCLC revealed that dysregulation of EGFR/MAP2K1/mTOR/YAP1 signaling pathways was associated with the progression, therapeutic resistance, immune-invasive phenotypes, and worse prognoses of NSCLC patients. Analysis of single-cell RNA sequencing datasets revealed that MAP2K1, mTOR, YAP1 and EGFR were predominantly located on monocytes/macrophages, Treg and exhaustive CD8 T cell, and are involved in M2 polarization within the TME of patients with primary and metastatic NSCLC which further implied gene’s role in remodeling the tumor immune microenvironment. A molecular-docking analysis revealed that NLOC-015A bound to YAP1, EGFR, MAP kinase/extracellular signal-related kinase kinase 1 (MEK1), and mTOR with strong binding efficacies ranging –8.4 to –9.50 kcal/mol. Interestingly, compared to osimertinib, NLOC-015 bound with higher efficacy to the tyrosine kinase (TK) domains of both T790M and T790M/C797S mutant-bearing EGFR. Our in vitro studies and sequencing analysis revealed that NLOC-015A inhibited the proliferation and oncogenic phenotypes of NSCLC cell lines with concomitant downregulation of expression levels of mTOR, EGFR, YAP1, and MEK1 signaling network. We, therefore, suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR, mTOR/NF-κB, YAP1, MEK1 in NSCLC.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

Who we are

Solutions
Plan
Contact us

What we do

Drug
Clinical Progress
Patent
Literature
Report
News