Optimization of Antitumor Modulators of Pre-mRNA Splicing

• Published in: Journal of medicinal chemistry Vol. 56; no. 24; pp. 10033 - 10044
• Main Authors: Lagisetti, Chandraiah, Palacios, Gustavo, Goronga, Tinopiwa, Freeman, Burgess, Caufield, William, Webb, Thomas R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.12.2013; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Chemistry, Medicinal; Cyclohexylamines - chemical synthesis; Cyclohexylamines - chemistry; Cyclohexylamines - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, SCID; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Pharmacology & Pharmacy; RNA Splicing - drug effects; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Spliceosomes - drug effects; Spliceosomes - genetics; Spliceosomes - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured; TARGET; AGENT; COMBINATIONS; FR901464; METABOLISM; SF3B; SPLICEOSOME; SUBSTANCES; MUTATIONS
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm401370h

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.