2. Academic Validation
  3. Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors

Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors

  • J Med Chem. 2019 Sep 26;62(18):8497-8510. doi: 10.1021/acs.jmedchem.9b00763.
I-Shan Hsieh 1,  Balraj Gopula 1 2,  Chi-Chi Chou 1,  Hsiang-Yi Wu 1,  Geen-Dong Chang 3,  Wen-Jin Wu 1,  Chih-Shiang Chang 2 4,  Po-Chen Chu 2 5,  Ching S Chen 6 7
Affiliations

Affiliations

  • 1 Institute of Biological Chemistry , Academia Sinica , Taipei 11529 , Taiwan.
  • 2 Drug Development Center , China Medical University , Taichung 40402 , Taiwan.
  • 3 Institute of Biochemical Sciences , National Taiwan University , Taipei 10617 , Taiwan.
  • 4 School of Pharmacy, College of Pharmacy, China Medical University , Taichung 40402 , Taiwan.
  • 5 Department of Cosmeceutics and Graduate Institute of Cosmeceutics , China Medical University , Taichung 40402 , Taiwan.
  • 6 Institute of New Drug Development , China Medical University , Taichung 40402 , Taiwan.
  • 7 Department of Medical Research , China Medical University Hospital, China Medical University , Taichung 40447 , Taiwan.
PMID: 31465224 DOI: 10.1021/acs.jmedchem.9b00763
Abstract

As Cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in Cancer therapy. Among various metabolic Enzymes examined, Pyruvate Kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of Cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for Cancer therapy.

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