title: Optimization of antitumor modulators of pre-mRNA splicing.
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.
authors: 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.
authors: Chandraiah
authors: C
authors: Lagisetti
authors: Gustavo
authors: G
authors: Palacios
authors: Tinopiwa
authors: T
authors: Goronga
authors: Burgess
authors: B
authors: Freeman
authors: William
authors: W
authors: Caufield
authors: Thomas R
authors: TR
authors: Webb
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics; D012326:RNA Splicing / Q000187:drug effects*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017381:Spliceosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C586721:5-((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; D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D013141:Spiro Compounds