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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 35, Number 12
BKCSDE 35(12)
December 20, 2014

Title	Synthesis and Biological Evaluation of Tetrapeptide Ketones as Reversible 20S Proteasome Inhibitors
Author	Muhammad Latif, Myoung Eun Jung, Kwangho Lee, Gildon Choi
Keywords	Proteasome, Carfilzomib, Ketones, Reversible and covalent
Abstract	Proteasome, a multicatalytic protease complex, has been validated as a promising therapeutic target in oncology. Carfilzomib (Kyprolis®), 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 Cterminus. 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 GI50 of 4.4 μM. Cytotoxic effects of 14-8 were further evaluated by cell cycle analysis and Western blotting, demonstrating activation of apoptotic pathways.
Page	3571 - 3575
Full Text	PDF

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