New Antitumor Substances, FR901463, FR901464 and FR901465. I. Taxonomy, Fermentation, Isolation, Physico-chemical Properties and Biological Activities.

Nakajima, Hidenori; Sato, Bunji; Fujita, Takashi; Takase, Shigehiro; Terano, Hiroshi; Okuhara, Masakuni

doi:10.7164/antibiotics.49.1196

Cited by 159 publications

(167 citation statements)

References 27 publications

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“…S4). It is worth noting that the optimum temperature for Fr9P activity matches the permissive growth temperature of <35°C for the producing organism FERM BP-3421 (21 ). The structures of these degradation products were further elucidated by NMR or by comparison with authentic standards (see below).…”

Section: Genomementioning

confidence: 79%

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Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

Eustáquio

Janso

Ratnayake

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Spliceostatins are bacterial natural products that show promising anticancer activity. Understanding how the bacterium makes spliceostatins will aid efforts toward a sustainable route for their production. Moreover, altering the chemical structure of a natural product is usually necessary to improve its pharmaceutical properties. For example, the parent spliceostatin molecule contains an unstable hemiketal chemical group. Contrary to previous hypotheses, we report on the identification of a dioxygenase enzyme responsible for hemiketal biosynthesis. Deletion of the corresponding dioxygenase gene led to a strain that produces exclusively spliceostatin congeners that are more stable than, and as active as, the parent compound, when derivatized to increase cell permeability. The strain generated in this study will be the basis for future development.

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Section: Genomementioning

confidence: 79%

“…no. 2663 but was recently reclassified as Burkholderia (21,22). A more stable, semisynthetic methyl ketal of 4 was later shown to inhibit the spliceosome, and it was thus termed spliceostatin A (Fig.…”

mentioning

confidence: 99%

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

Eustáquio

Janso

Ratnayake

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Structure-activity relationship (SAR) data for the three compounds and related molecules have been steadily emerging (Sakai et al 2002;Mizui et al 2004;Lagisetti et al 2008Lagisetti et al , 2013Lagisetti et al , 2014Albert et al 2009;Fan et al 2011;Gundluru et al 2011;Muller et al 2011;Villa et al 2012Villa et al , 2013Gao et al 2013;Ghosh and Chen 2013;Arai et al 2014;Effenberger et al 2014;Ghosh et al 2014a,b,c;He et al 2014). SSA (1), which is similar to FR901464 (Nakajima et al 1996b), meayamycin (Albert et al 2009), thailanstatins (Liu et al 2013), and sudemycins (Fan et al 2011), differs in structure relative to the other two compounds. PB (2), which is related to E7107 and FD-895 (Kotake et al 2007;Villa et al 2012), and HB (3), a member of GEX1 family (Sakai et al 2002), share a similar side chain, but have different ring structures (macrolide vs. tetrahydropyran).…”

Section: Introductionmentioning

confidence: 94%

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

Effenberger

Urabe

Prichard

et al. 2016

RNA

102

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The protein SF3B1 is a core component of the spliceosome, the large ribonucleoprotein complex responsible for pre-mRNA splicing. Interest in SF3B1 intensified when tumor exome sequencing revealed frequent specific SF3B1 mutations in a variety of neoplasia and when SF3B1 was identified as the target of three different cancer cell growth inhibitors. A better mechanistic understanding of SF3B1's role in splicing is required to capitalize on these discoveries. Using the inhibitor compounds, we probed SF3B1 function in the spliceosome in an in vitro splicing system. Formerly, the inhibitors were shown to block early steps of spliceosome assembly, consistent with a previously determined role of SF3B1 in intron recognition. We now report that SF3B1 inhibitors also interfere with later events in the spliceosome cycle, including exon ligation. These observations are consistent with a requirement for SF3B1 throughout the splicing process. Additional experiments aimed at understanding how three structurally distinct molecules produce nearly identical effects on splicing revealed that inactive analogs of each compound interchangeably compete with the active inhibitors to restore splicing. The competition indicates that all three types of compounds interact with the same site on SF3B1 and likely interfere with its function by the same mechanism, supporting a shared pharmacophore model. It also suggests that SF3B1 inhibition does not result from binding alone, but is consistent with a model in which the compounds affect a conformational change in the protein. Together, our studies reveal new mechanistic insight into SF3B1 as a principal player in the spliceosome and as a target of inhibitor compounds.

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“…Several compounds are available for this purpose, [13][14][15][16] including meayamycin B 17,18 and the structurally related spliceostatin A (SSA). 16 SSA is a synthetically modified analog of the natural product FR901464, 19 while meayamycin B is prepared by total synthesis. 20 SSA binds to SF3B1 and possibly other members of the splicing factor 3 complex and targets normal splicing in the cell, promoting alternative gene splicing, accumulation of unspliced mRNAs in the nucleus and a decrease in translation.…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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New Antitumor Substances, FR901463, FR901464 and FR901465. I. Taxonomy, Fermentation, Isolation, Physico-chemical Properties and Biological Activities.

Cited by 159 publications

References 27 publications

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

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