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

Abstract

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.