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

  • J Med Chem. 2025 Jun 12;68(11):11406-11418. doi: 10.1021/acs.jmedchem.5c00376.
Marcian E Van Dort  1  2 ,  Lucas McDonald  1  2 ,  Youngsoon Jang  1  2 ,  Kevin Heist  1  2 ,  Christopher A Bonham  1  2 ,  Kamryn Abraskin  1  2 ,  Thomas L Chenevert  1  2 ,  Brian D Ross  1  2  3
Affiliations
  • 1. Center for Molecular Imaging, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
PMID: 40375738 DOI: 10.1021/acs.jmedchem.5c00376
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 (A375), with a corresponding decrease in cellular proliferation and migration. Treatment of mice with LP-65 (40 mg/kg) having a myeloproliferative neoplasm, myelofibrosis, revealed down modulation of in vivo signaling pathways and therapeutic efficacy.

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