Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors

I. Shan Hsieh, Balraj Gopula, Chi Chi Chou, Hsiang Yi Wu, Geen Dong Chang, Wen Jin Wu, Chih Shiang Chang, Po Chen Chu, Ching S. Chen

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)8497-8510
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number18
DOIs
StatePublished - 26 Sep 2019
Externally publishedYes

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