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

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature and limited treatment options.
• Pyruvate kinase M2 (PKM2) is frequently overexpressed in TNBC, promoting tumor progression by enhancing glycolysis, lactate production, and inhibiting autophagy.

Purpose of the Study:

• To rationally design and develop a novel small molecule inhibitor targeting PKM2 for the treatment of TNBC.
• To evaluate the preclinical efficacy of the developed compound, designated as 7d, in vitro and in vivo.

Main Methods:

• Enzyme assays were employed to identify PKM2 inhibitors in the nanomolar range.
• In vitro validation included 2D/3D cell cultures, lactate release assays, and qRT-PCR.
• Surface plasmon resonance (SPR) was used for binding analysis.
• In vivo efficacy was assessed by comparing tumor regression of 7d against lapatinib in a preclinical model.

Main Results:

• A novel imidazopyridine-based thiazole derivative, 7d, was identified as a potent PKM2 inhibitor with favorable drug-like properties.
• Preclinical studies confirmed the inhibitory activity of 7d against PKM2.
• In vivo studies demonstrated superior tumor regression by 7d compared to the standard drug lapatinib.

Conclusions:

• Compound 7d represents a potent and effective PKM2 inhibitor with significant therapeutic potential for TNBC.
• The study highlights a successful lead-based drug design strategy targeting PKM2 for cancer therapy.
• 7d shows promise as a novel chemotherapeutic agent against triple-negative breast cancer.