title: Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing.
abstract: Two unrelated bacterial natural products, FR901464 and pladienolide B, have previously been shown to have significant antitumor activity in vivo. These compounds target the SF3b subunit of the spliceosome, with a derivative of pladienolide (E7107) entering clinical trials for cancer. However, due to the structural complexity of these molecules, their research and development has been significantly constrained. We have generated a set of novel analogues (Sudemycins) that possess the pharmacophore that is common to FR901464 and pladienolide, via a flexible enantioselective route, which allows for the production of gram quantities of drug. These compounds demonstrate cytotoxicity toward human tumor cell lines in culture and exhibit antitumor activity in a xenograft model. Here, we present evidence that Sudemycins are potent modulators of alternative splicing in human cells, both of endogenous genes and from minigene constructs. Furthermore, levels of alternative splicing are increased in tumor cells relative to normal cells, and these modifications can be observed in human tumor xenografts in vivo following exposure of animals to the drug. In addition, the change in the splicing pattern observed with the Sudemycins are similar to that observed with Spliceostatin A, a molecule known to interact with the SF3b subunit of the spliceosome. Hence, we conclude that Sudemycins can regulate the production of alternatively spliced RNA transcripts and these alterations are more prevalent in tumors, as compared to normal cells, following drug exposure. These studies suggest that modulation of alternative splicing may play a role in the antitumor activity of this class of agents.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, United States.
authors.forename: Liying
authors.initials: L
authors.lastname: Fan
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Lagisetti
authors.forename: Carol C
authors.initials: CC
authors.lastname: Edwards
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008968:Molecular Conformation; D008970:Molecular Weight; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C104486:FR 901464; D011714:Pyrans; D012333:RNA, Messenger; D013141:Spiro Compounds; C553684:spliceostatin A; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2