Total Synthesis of 6-Deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 Cancer Cell Line

Arai, Kenzo; Buonamici, Silvia; Chan, Betty; Corson, Laura; Endo, Atsushi; Gerard, Baudouin; Hao, Ming‐Hong; Karr, Craig; Kira, Kazunobu; Lee, Linda; Xiang, Liangzhong; Lowe, Jason T.; Luo, Tuoping; Marcaurelle, Lisa A.; Mizui, Yoshiharu; Nevalainen, Marta; O’Shea, Morgan Welzel; Park, Eun Sun; Perino, Samantha; Prajapati, Sudeep; Shan, Mingde; Smith, Peter G.; Tivitmahaisoon, Parcharee; Wang, John Yuan; Warmuth, Markus; Wu, Kuo-Ming; Yu, Lihua; Zhang, Huiming; Zheng, Guo-Zhu; Keaney, Gregg F.

doi:10.1021/ol502556c

Cited by 22 publications

(27 citation statements)

References 47 publications

(24 reference statements)

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“…Efforts should be made to systematically identify the oncogenic drivers generated by weak splicing events. Other types of cancers that could be specifically treated by the use of low dose splicing modulators are the ones harboring (a) mutation(s) within speciific splicing factors serving as small molecule targets, such as SF3B1 [44], or tumors that are globally capable of increasing the splicing burden [17]. …”

Section: Discussionmentioning

confidence: 99%

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Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Salton

Misteli

2016

Trends in Molecular Medicine

137

133

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Pre-mRNA splicing is a fundamental process in mammalian gene expression and alternative RNA splicing plays a considerable role in generating protein diversity. RNA splicing events are key to the pathology of numerous diseases, including cancers. Some tumors are molecularly addicted to specific RNA splicing isoforms making interference with pre-mRNA processing a viable therapeutic strategy. Several RNA splicing modulators have been recently characterized showing promise in pre-clinical studies. While the targets of most splicing modulators are constitutive RNA processing components, with undesirable side effects, selectivity for individual splicing events has been observed. Given the high prevalence of splicing defects in cancer, small molecule modulators of RNA processing represent a novel therapeutic strategy in cancer treatment. Here, we review their reported effects, potential mechanisms, and limitations.

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Section: Discussionmentioning

confidence: 99%

“…Other splicing modulators were subsequently extracted from different strains of bacteria, namely, Pladienolides from Streptomyces platensis [41–44] and GEX1, from Streptomyces sp. [45, 46], and both have the same mechanism of action as SSA [47, 48].…”

Section: Discovery Of Small Molecule Splicing Modulatorsmentioning

confidence: 99%

Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Salton

Misteli

2016

Trends in Molecular Medicine

137

133

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“…Although these earliest natural compounds showed promising anti-cancer properties in various in vitro and in vivo studies with half-maximal inhibitory concentrations (IC50s) in the low nanomolar ranges, they were chemically unstable and thus unsuitable for therapeutic purposes. Total synthesis 47-51 and further analogue efforts resulted in the successful development of additional compounds with improved stability, most notably E7107 52 (an analogue of pladienolide B), spliceostatin A (SSA; from FR901464) 53 and the sudemycins 54 (Table). …”

Section: Methods To Target Splicing In Cancermentioning

confidence: 99%

Therapeutic targeting of splicing in cancer

Lee

Abdel‐Wahab

2016

Nat Med

465

492

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A number of recent studies have highlighted that splicing is frequently altered in cancer and that mutations affecting splicing of key cancer-associated genes as well as mutations and copy-number changes affecting spliceosomal proteins themselves are enriched in cancer. In parallel, there is also accumulating evidence that several molecular subtypes of cancer are highly dependent on wildtype splicing function for cell survival. These findings have resulted in a growing interest in targeting splicing catalysis, splicing regulatory proteins, and/or individual key altered splicing events in the treatment of cancer. In this review we present strategies that exist and are in development to target altered dependency on the spliceosome as well as aberrant splicing in cancer. These include drugs to target global splicing in cancer subtypes which are preferentially dependent on wildtype splicing for survival, methods to alter post-translational modifications of splice regulatory proteins, and strategies to modulate pathologic splicing events and protein/RNA interactions in cancer.

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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.…”

Section: Introductionmentioning

confidence: 99%

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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Total Synthesis of 6-Deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 Cancer Cell Line

Cited by 22 publications

References 47 publications

Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Therapeutic targeting of splicing in cancer

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

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