2. Academic Validation
  3. Development of isoselenazolium chlorides as selective pyruvate kinase isoform M2 inhibitors

Development of isoselenazolium chlorides as selective pyruvate kinase isoform M2 inhibitors

  • Eur J Med Chem. 2023 Sep 5;257:115504. doi: 10.1016/j.ejmech.2023.115504.
Pavels Dimitrijevs 1,  Marina Makrecka-Kuka 1,  Agnieszka Bogucka 2,  Marko Hyvönen 2,  Teodors Pantelejevs 1,  Pavel Arsenyan 3
Affiliations

Affiliations

  • 1 Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006, Riga, Latvia.
  • 2 Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Ct Rd, Cambridge, CB2 1GA, UK.
  • 3 Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006, Riga, Latvia. Electronic address: pavel@osi.lv.
PMID: 37216812 DOI: 10.1016/j.ejmech.2023.115504
Abstract

Alterations in Cancer metabolic pathways open up an opportunity for targeted and effective elimination of tumor cells. Pyruvate Kinase M2 (PKM2) is predominantly expressed in proliferating cells and plays an essential role in directing glucose metabolism in Cancer. Here, we report the design of novel class of selective PKM2 inhibitors as anti-cancer agents and their mechanism of action. Compound 5c being the most active with IC50 = 0.35 ± 0.07 μM, also downregulates PKM2 mRNA expression, modulates mitochondrial functionality, induces oxidative burst and is cytotoxic for various Cancer types. Isoselenazolium chlorides have an unusual mechanism of PKM2 inhibition, inducing a functionally deficient tetrameric assembly, while exhibiting a competitive inhibitor character. The discovery of robust PKM2 inhibitors not only offers candidates for Anticancer therapy but is also crucial for studying the role of PKM2 in Cancer.

Keywords

Cancer; Metabolic reprogramming; Pyruvate kinase M2; Selenium.

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