The spliceosome as a target of novel antitumour drugs

1] Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain. [2] Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain. [3].
Nature Reviews Drug Discovery (Impact Factor: 41.91). 11/2012; 11(11):847-59. DOI: 10.1038/nrd3823
Source: PubMed


Several bacterial fermentation products and their synthetic derivatives display antitumour activities and bind tightly to components of the spliceosome, which is the complex molecular machinery involved in the removal of introns from mRNA precursors in eukaryotic cells. The drugs alter gene expression, including alternative splicing, of genes that are important for cancer progression. A flurry of recent reports has revealed that genes encoding splicing factors, including the drug target splicing factor 3B subunit 1 (SF3B1), are among the most highly mutated in various haematological malignancies such as chronic lymphocytic leukaemia and myelodysplastic syndromes. These observations highlight the role of splicing factors in cancer and suggest that an understanding of the molecular effects of drugs targeting these proteins could open new perspectives for studies of the spliceosome and its role in cancer progression, and for the development of novel antitumour therapies.

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    • "No. 2663) (He et al., 2014; Nakajima et al., 1997). A more stable, semi-synthetic analog of FR901464 was later shown to target the spliceosome – an emerging mode of action for anticancer therapy (Bonnal et al., 2012) – and it was thus termed spliceostatin A (6) (Kaida et al., 2007). Compounds containing a terminal carboxylic acid (1–3) instead of the hemiketal present in 4 and 5 were later isolated from FERM BP-3421 and from Burkholderia sp. "
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    ABSTRACT: A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. Spliceostatins are polyketide-nonribosomal peptide natural products that bind to the spliceosome, an emerging target in cancer therapy. The wild-type bacterium Burkholderia sp. FERM BP-3421 produces a suite of spliceostatin congeners with varying biological activities and physiological stabilities. Hemiketal compounds such as FR901464 were the first to be described. Due to its improved properties, we were particularly interested in a carboxylic acid precursor analog that was first reported from Burkholderia sp. MSMB 43 and termed thailanstatin A. Inactivation of the iron/α-ketoglutarate-dependent dioxygenase gene fr9P had been shown to block hemiketal biosynthesis. However, a 4-deoxy congener of thailanstatin A was the main product seen in the dioxygenase mutant. We show here that expression of the cytochrome P450 gene fr9R is a metabolic bottle neck, as use of an L-arabinose inducible system led to nearly complete conversion of the 4-deoxy analog to the target molecule. By integrating fermentation media development approaches with biosynthetic engineering, we were able to improve production titers of the target compound >40-fold, going from the starting ~60mg/L to 2.5g/L, and to achieve what is predominantly a single component production profile. These improvements were instrumental in enabling preclinical development of spliceostatin analogs as chemotherapy.
    Preview · Article · Nov 2015 · Metabolic Engineering
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    • "Alternative splicing leads to different isoforms of vascular endothelial growth factor, which is responsible for either inhibiting or facilitating the formation of blood vessels, and is known to be a key event in tumor growth and metastasis (Bonnal et al. 2012). mRNA splicing is performed by spliceosome, a macromolecular complex composed of five small nuclear ribonucleoproteins (snRNPs) (U1, U2, U4, U5, and U6) (Lagisetti et al. 2013). "
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    ABSTRACT: Herboxidiene is a polyketide with a diverse range of activities, including herbicidal, anti-cholesterol, and pre-mRNA splicing inhibitory effects. Thus, production of the compound on the industrial scale is in high demand, and various rational metabolic engineering approaches have been employed to enhance the yield. Directing the precursors and cofactors pool toward the production of polyketide compounds provides a rationale for developing a good host for polyketide production. Due to multiple promising biological activities, the production of a number of herboxidiene derivatives has been attempted in recent years in a search for the key to improve its potency and to introduce new activities. Structural diversification through combinatorial biosynthesis was attempted, utilizing the heterologous expression of substrate-flexible glucosyltransferase (GT) and cytochrome P450 in Streptomyces chromofuscus to generate structurally and functionally diverse derivatives of herboxidiene. The successful attempt confirmed that the strain was amenable to heterologous expression of foreign polyketide synthase (PKS) or post-PKS modification genes, providing the foundation for generating novel or hybrid polyketides.
    Full-text · Article · Aug 2015 · Applied Microbiology and Biotechnology
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    • "Recently, mutations in SF3B1 have been linked to various types of cancer (Bonnal et al., 2012), and these mutations are correlated with poor prognosis in patients with chronic lymphocytic leukemia and myelodysplastic disorders (Quesada et al., 2012; Yoshida et al., 2011). Whether the pathogenesis of these mutations is a consequence of reduced levels of functional protein or dominant-negative effects remains unclear. "
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    ABSTRACT: Much remains unknown concerning the mechanism by which the splicing machinery pinpoints short exons within intronic sequences and how splicing factors are directed to their pre-mRNA targets. One probable explanation lies in differences in chromatin organization between exons and introns. Proteomic, co-immunoprecipitation, and sedimentation analyses described here indicate that SF3B1, an essential splicing component of the U2 snRNP complex, is strongly associated with nucleosomes. ChIP-seq and RNA-seq analyses reveal that SF3B1 specifically binds nucleosomes located at exonic positions. SF3B1 binding is enriched at nucleosomes positioned over short exons flanked by long introns that are also characterized by differential GC content between exons and introns. Disruption of SF3B1 binding to such nucleosomes affects splicing of these exons similarly to SF3B1 knockdown. Our findings suggest that the association of SF3B1 with nucleosomes is functionally important for splice-site recognition and that SF3B1 conveys splicing-relevant information embedded in chromatin structure. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Cell Reports
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