Identification of Parthenolide Dimers as Activators of Pyruvate Kinase M2 in Xenografts of Glioblastoma Multiforme in Vivo

Herein
we detail the discovery of a series of parthenolide dimers
as activators of PKM2 and evaluation of their anti-GBM activities.
The most promising compound 5 showed high potency to
activate PKM2 with an AC50 value of 15 nM, inhibited proliferation
and metastasis, and induced apoptosis of GBM cells. Compound 5 could promote tetramer formation of PKM2 and reduce nucleus
translocation of PKM2 in GBM cells without influence on the expression
of total PKM2, thereby inhibiting the STAT3 signal pathway in vitro
and in vivo. PKM2 knockdown assay demonstrated that the anti-GBM effect
of 5 mainly depended on the expression of PKM2 in vitro
and in vivo. Compound 16, a prodrug of 5, markedly suppressed U118 tumor xenograft growth and reduced the
weight of tumor. On the basis of these investigations, we propose
that 16 might be considered as a promising lead compound
for discovery of anti-GBM drugs.