Parthenolide Derivatives as PKM2 Activators Showing Potential in Colorectal Cancer

As a vital kinase in the glycolysis
system, PKM2 is extensively
expressed in colorectal cancer (CRC) to support the energy and biosynthetic
needs. In this study, we designed a series of parthenolide (PTL) derivatives
through a stepwise structure optimization, and an excellent derivate 29e showed good activity on PKM2 (AC50 = 86.29
nM) and displayed significant antiproliferative activity against HT29
(IC50 = 0.66 μM) and SW480 (IC50 = 0.22
μM) cells. 29e decreased the expression of total
PKM2, prevented nucleus translocation of PKM2 dimer, and inhibited
PKM2/STAT3 signaling pathway. 29e remarkably increased
OCR and decreased the extracellular acidification rate (ECAR). The
antiproliferative effect of 29e depended on PKM2, and
the Cys424 of PKM2 was the key binding site. Furthermore, 29e significantly suppressed tumor growth in the HT29 xenograft model
without obvious toxicity. These outcomes demonstrate that 29e is a promising drug candidate for the treatment of CRC.