The First Splicing Inhibitors

SSA constitutes a methyl ketal derivative of a natural product named FR901464 and was originally isolated from a Pseudomonas sp. fermentation broth [24, 25]. Before identification of the molecule s true mechanism, FR901464 had already attracted attention as a potent activator of viral promoters, as well as having visible antitumor activity. It inhibited the growth of various cancer cell lines at low nanomolar concentrations and extended the life span of tumor-bearing mice. 

However, the activation of viral promoters hinted more at an involvement in cell signaling and gave no indication of the molecule s actual mechanism. 

It had been observed that FR901464 treatment led to cell cycle arrest in G1 and G2/M phases and buildup of a truncated form of the cyclin dependent kinase (CDK) inhibitor p27, dubbed p27. The derivative SSA remains as potent as its parent compound but is chemically significantly more stable, thus making for a much more convenient research tool. 

As for pladienolide, a related Streptomyces natural product, herboxidiene (also called GEXIA) had been identified previously and proved amenable to full synthesis [34-36]. 

Both SSA and pladienolide present a bona fide example for target identification in chemical biology. Both molecules proved amenable to derivatization, without losing too much activity or going off-target. 

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