Mechanistic Investigation of Thiazole-Based Pyruvate Kinase M2 Inhibitor Causing Tumor Regression in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a deadly breast
cancer
with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting
enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed
PKM2 amplifies glucose uptake, enhances lactate production, and suppresses
autophagy, thereby expediting the progression of oncogenic processes.
A high mortality rate demands novel chemotherapeutic regimens at once.
Herein, we report the rational development of an imidazopyridine-based
thiazole derivative 7d as an anticancer agent inhibiting
PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties
emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional
(3D) cell cultures, lactate release assay, surface plasmon resonance
(SPR), and quantitative real-time polymerase chain reaction (qRT-PCR)
validated 7d preclinically. In vivo, 7d outperformed lapatinib in tumor regression. This investigation
introduces a lead-based approach characterized by its clear-cut chemistry
and robust efficacy in designing an exceptionally potent inhibitor
targeting PKM2, with a focus on combating TNBC.