Structure of FD-895 Revealed through Total Synthesis

Villa, Reymundo; Mandel, Alexander; Jones, Bradley M.; Clair, James J. La; Burkart, Michael D.

doi:10.1021/ol3023006

Cited by 44 publications

(64 citation statements)

References 28 publications

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“…Until recently, structural complexity constrained development. The natural product pladienolide B and derivatives, including FD-895 (Villa et al, 2012), demonstrate poor stability in aqueous and biological media. The short half lives ( t 1/2 ≤15 min) of these compounds and toxicity (Hong et al, 2014) arising from hydrolyzed seco -acids highlight the need for development of stabilized and selective spliceosome-targeted compounds.…”

Section: Resultsmentioning

confidence: 99%

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

et al. 2016

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SUMMARY Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSC) in secondary acute myeloid leukemia (sAML). While acquisition of clonal DNA mutations have been linked to increased rates of sAML for individuals over 60, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA-sequencing and splice isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged HSPCs, compared with malignant MDS and AML progenitors. In splicing reporter assays and in pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. By comparing splice isoform biomarkers of normal HSPC aging with those of LSC generation, splicing modulation may be employed safely and effectively to prevent relapse – the leading cause of leukemia-related mortality.

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Section: Resultsmentioning

confidence: 99%

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

et al. 2016

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“…However, it is notable that a hydroxyl group is also present at C16 in two other PB analogs (pladienolide D and E7107), both of which mimic the effects of PB on splicing and cells with similar potencies (8,15). Also, isomerization of the C16-C17 bond in the context of FD-895, another related natural product with an additional hydroxyl group at C17 (31), has limited effect on the cytotoxicity of the compound (29,32). More studies focusing on each position independently will be required to clear up the contribution of functional groups to PB activity at these sites.…”

Section: Discussionmentioning

confidence: 99%

Coherence between Cellular Responses and in Vitro Splicing Inhibition for the Anti-tumor Drug Pladienolide B and Its Analogs

Effenberger

Anderson

Bray

et al. 2014

Journal of Biological Chemistry

105

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Background: Pladienolide B is a complex natural product that potently inhibits pre-mRNA splicing. Results: The same molecular features of pladienolide B are required for the drug's effects on cell growth, morphology, and splicing. Conclusion: Simplified synthesis and modification of active pladienolide B is possible. Significance: Pladienolide B analogs can be used to study the relationship between splicing and cancer cell function.

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“…However, these compounds demonstrate poor metabolic stability and short half-lives in vivo, excluding them from entering clinical evaluation (99,100). 17S-FD-895, an analog of FD-895, was synthesized through the combination of total synthesis and synthetic methods, demonstrating improved stability and on-target effect (101). This new spliceosome targeting compound was evaluated in different sAML models and showed potent efficacy in inhibition of AML LSC and disruption of AML maintenance in vitro and in mouse xenograft models (98).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

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The spliceosome, the cellular splicing machinery, regulates RNA splicing of messenger RNA precursors (pre-mRNAs) into maturation of protein coding RNAs. Recurrent mutations and copy number changes in genes encoding spliceosomal proteins and splicing regulatory factors have tumor promoting or suppressive functions in hematological malignancies, as well as some other cancers. Leukemia stem cell (LSC) populations, although rare, are essential contributors of treatment failure and relapse. Recent researches have provided the compelling evidence that link the erratic spicing activity to the LSC phenotype in acute myeloid leukemia (AML). In this article, we describe the diverse roles of aberrant splicing in hematological malignancies, particularly in AML and their contributions to the characteristics of LSC. We review these promising strategies to exploit the addiction of aberrant spliceosomal machinery for anti-leukemic therapy with aim to eradicate LSC. However, given the complexity and plasticity of spliceosome and not fully known functions of splicing in cancer, the challenges facing the development of the therapeutic strategies targeting RAN splicing are highlighted and future directions are discussed too.

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Structure of FD-895 Revealed through Total Synthesis

Cited by 44 publications

References 28 publications

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

Coherence between Cellular Responses and in Vitro Splicing Inhibition for the Anti-tumor Drug Pladienolide B and Its Analogs

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

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