Thiazole-Based Tumor Pyruvate Kinase M2 Inhibitors: A Paradigm-Shifting Therapeutic Strategy Targeting Metabolic and Microbial Synergy in Colorectal Cancer

Colorectal cancer (CRC) remains a major global health
burden, with
current treatments primarily focused on eradicating cancer cells.
However, chemotherapy-induced gut dysbiosis exacerbates inflammation
and disease progression, necessitating innovative therapeutic strategies.
While various metabolic inhibitors and microbiome-modulating approaches
have been explored separately, no reported agent to date simultaneously
targets both cancer cell survival and gut microbiome restoration.
We designed thiazole-based pyruvate kinase M2 (PKM2) inhibitors, hypothesizing
that selective modulation may suppress tumor growth while restoring
gut microbial balance. 10j selectively inhibited PKM2
in a cell-free assay (0.01 ± 0.0009 μM) and in CRC cells
(4.21 ± 0.04 μM), disrupting key pathways driving CRC progression.
Remarkably, metagenomic analysis revealed that 10j restored
gut microbiota balance. These findings suggest that dual-function
anticancer agents, which kill cancer cells while simultaneously restoring
gut microbiota, represent an unexplored therapeutic avenue. Thiazole-based
PKM2 inhibitors are pioneering this novel strategy in CRC treatment.