Tanshinone IIA derivatives inhibits colorectal cancer growth by targeting pyruvate kinase M2.

Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, is frequently overexpressed in colorectal cancer (CRC) and has emerged as a promising therapeutic target. In this study, a series of Tanshinone IIA derivatives were designed and synthesized through simultaneous modification of rings A and D, and their anti-CRC activities were evaluated. The optimized derivative 23 exhibited PKM2 activation (AC = 92.12 nM) and significantly inhibited the proliferation of CRC cells. Molecular docking analysis revealed that the piperidinothiophene moiety in 23 strengthens binding through a salt bridge interaction with Asp295. Furthermore, 23 suppressed the PKM2/STAT3 signaling pathway both in vitro and in vivo. Together, these findings highlight derivative 23 as a promising anticancer candidate for the treatment of CRC.