Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Synthesis and Biological Evaluation of Tetrapeptide Ketones as Reversible 20S Proteasome Inhibitors

  • Latif, Muhammad (Drug Discovery Division, Korea Research Institute of Chemical Technology) ;
  • Jung, Myoung Eun (Drug Discovery Division, Korea Research Institute of Chemical Technology) ;
  • Lee, Kwangho (Drug Discovery Division, Korea Research Institute of Chemical Technology) ;
  • Choi, Gildon (Drug Discovery Division, Korea Research Institute of Chemical Technology)
  • Received : 2014.07.15
  • Accepted : 2014.08.20
  • Published : 2014.12.20
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Abstract

Proteasome, a multicatalytic protease complex, has been validated as a promising therapeutic target in oncology. Carfilzomib (Kyprolis$^{(R)}$), a tetrapeptide epoxyketone, irreversibly inhibits the chymotrypsin-like (CT-L) activity of the proteasome and has been recently approved for multiple myeloma treatment by FDA. A chemistry effort was initiated to discover the compounds that are reversibly inhibit the proteasome by replacing the epoxyketone moiety of carfilzomib with a variety of ketones as reversible and covalent warheads at the C-terminus. The newly synthesized compounds exhibited significant inhibitory activity against CT-L activity of the human 20S proteasome. When the compounds were tested for cancer cell viability, 14-8 was found to be most potent in inhibiting Molt-4 acute lymphoblastic leukemia cell line with a $GI_{50}$ of $4.4{\mu}M$. Cytotoxic effects of 14-8 were further evaluated by cell cycle analysis and Western blotting, demonstrating activation of apoptotic pathways.

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