Synthesis and Biological Evaluation of MEK/mTOR Multifunctional Inhibitors as Novel Anticancer Agents.

ABSTRACT: The mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) signaling nodes play a crucial role in many human cancers. Due to the molecular reciprocity between MAPK and mTOR signaling nodes, development of compounds with multikinase targeting was explored. A series of mTOR inhibitor analogs of AZD8055 and AZD2014 were designed to allow for covalent linking to a potent MAPK kinase (MEK) inhibitor to produce a single, bivalent chemical entity. Dual-acting agents (i.e., compound LP-65) were synthesized displaying high in vitro inhibition of both MEK (IC₅₀ = 83.2 nM) and mTOR (IC₅₀ = 40.5 nM). Additionally, compound LP-65 demonstrated significant modulation of MEK and mTOR signaling activity in human glioma cells (D54) and human melanoma cells (

SUBMITTER: Van Dort ME 

PROVIDER: S-EPMC12435495 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature