Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cyclohexylamines / chemical synthesis
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Cyclohexylamines / chemistry
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Cyclohexylamines / pharmacology*
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Dose-Response Relationship, Drug
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Drug Discovery
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Drug Screening Assays, Antitumor
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HeLa Cells
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Humans
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Male
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Mice
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Mice, SCID
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Molecular Structure
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Neoplasms, Experimental / drug therapy*
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Neoplasms, Experimental / genetics
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RNA Splicing / drug effects*
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Spliceosomes / drug effects
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Spliceosomes / genetics
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Spliceosomes / metabolism
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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5-((4-(5-(7,7-dimethyl-1,6-dioxaspiro(2.5)octan-5-yl)-3-methylpenta-2,4-dien-1-yl)cyclohexyl)amino)-5-oxopent-3-en-2-yl methylcarbamate
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Antineoplastic Agents
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Cyclohexylamines
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Spiro Compounds