2. Academic Validation
  3. Mechanistic Investigation of Thiazole-Based Pyruvate Kinase M2 Inhibitor Causing Tumor Regression in Triple-Negative Breast Cancer

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

  • J Med Chem. 2024 Feb 26. doi: 10.1021/acs.jmedchem.3c01512.
Rudradip Das 1,  Priyanka Pulugu 2,  Aditya A Singh 3,  Deep Rohan Chatterjee 1,  Shraddha Baviskar 4,  Het Vyas 1,  Santosh Kumar Behera 4,  Akshay Srivastava 2,  Hemant Kumar 3,  Amit Shard 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Opposite Airforce station, Palaj, Gandhinagar, Gujarat 382355, India.
  • 2 Department of Medical Devices, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Opposite Airforce station, Palaj, Gandhinagar, Gujarat 382355, India.
  • 3 Department of Pharmacology and Toxicology, (NIPER-A) National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Opposite Airforce station, Palaj, Gandhinagar, Gujarat 382355, India.
  • 4 Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Opposite Airforce station, Palaj, Gandhinagar, Gujarat 382355, India.
PMID: 38408027 DOI: 10.1021/acs.jmedchem.3c01512
Abstract

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.

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