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J Med Chem. 2013 Dec 27;56(24):10033-44. doi: 10.1021/jm401370h. Epub 2013 Dec 11.

Optimization of antitumor modulators of pre-mRNA splicing.

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Department of Chemical Biology and Therapeutics, ‡Preclinical PK Shared Resource, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105-2794, United States.


The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously, natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1). We report the optimization of a class of tumor-selective spliceosome modulators that demonstrate significant in vivo antitumor activity. This optimization culminated in the discovery of sudemycin D6, which shows potent cytotoxic activity in the melanoma line SK-MEL-2 (IC50 = 39 nM) and other tumor cell lines, including JeKo-1 (IC50 = 22 nM), HeLa (IC50 = 50 nM), and SK-N-AS (IC50 = 81 nM). We also report improved processes for the synthesis of these compounds. Our work supports the idea that sudemycin D6 is worthy of further investigation as a novel preclinical anticancer agent with application in the treatment of numerous human cancers.

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