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

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.