Splicing pladienolide

While the identification of SF3b was an impressive start, there is some concern over the considerable (645-fold) loss of activity in the Eisai probes prepared at C7. While these probes were used to identify the splicing factor SF3b, it is possible the lack in activity of Eisai s probe molecules failed to provide a complete description of the targets of the pladienolides. In addition, the mode of action of pladienolide B has yet to be directly... 

Kotake, Y Sagane, K Owa, T et al. (2007). Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat. Chem. Biol, 3, 570-575. 

Before the discovery of spliceostatin A (SSA) and pladienolide B, the spliceo-some had not been seriously considered as a potential drug target [3,4]. Naturally, identification of the first inhibitors allowed further dissection of the splicing apparatus and investigation of the cellular consequences of splicing dysfunction. 

In 2007, two papers were published back to back, each reporting the identification of a small-molecule inhibitor of the spliceosome [3,4]. Since the initial description of SSA and pladienolide B, a number of further splicing inhibitors have been discovered and opened a new and active field of investigation (Figure 22.2). Besides novelty, these molecules have proved to be potent probes into cellular processes, while also holding clinical promise. 

Figure 22.2 Ovennew of the splicing inhibitors discussed. FR901464 and derivatives are listed on the left, pladienolide and relatives on the right with the artificial inhibitor containing elements of both FR901464 and pladienolide, sudemycin in the middle. Herboxidiene/GEXl A and isoginkgetin are at the bottom.

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