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Spliceosome Modulators as Antitumor Lead Compounds
SRI's Webb Laboratory is designing new, readily prepared synthetic compounds that are active against an important recently discovered anticancer target.
The spliceosome—a complex molecular machine—is an important emerging target for cancer therapy that has only recently been uncovered and remains to be significantly exploited. Development of highly selective anti-tumor agents continues to be a challenge in drug discovery, which has motivated researchers to search for new molecular targets that allow for discovery of more selective anticancer agents than was possible with older toxic traditional chemotherapeutic agents, or even with the new generation of targeted cancer drugs that do not lead to lasting cures.
As part of a major research program funded by the National Cancer Institute and initiated in 2007, scientists in SRI's Webb Laboratory have been helping to lead a significant international effort to develop new drugs by synthetically modifying a recently discovered class of naturally occurring bacterially derived small molecules. After years of concentrated effort and many refinements, this work has culminated in development of a manmade drug candidate, sudemycin D6, which shows significant promise against several classes of cancers.
A recent discovery showed that several natural products (including pladienolide, FR901464, and herboxidiene) act by targeting the SF3b subunit of the spliceosome, and more specifically the SF3B1 protein. Recurrent mutations in the SF3B1 gene have recently been found in numerous cancers and appear to drive the process of oncogenesis in a entirely novel and unexpected way, which is only starting to be understood. The fact that aberrations of spliceosome action may lead to oncogenesis may be related to the observation that several of the splicing modulatory active natural products show such promising activity in certain in vivo anti-tumor models.
In particular, pladienolide and analogs have shown striking in vivo anti-tumor selectivity and efficacy, with a pronounced therapeutic window. However these natural products, and analogs derived from them, are synthetically quite complex. It can readily be concluded that the discovery of more facile routes to active simplified compounds that work by modulation of the spliceosome is an important goal for the drug discovery community at large.
We have recently reported the optimization of a class of novel highly stabilized synthetic analogs of FR901464 (the sudemycins) that possess in vitro cytotoxicity IC50 values as low as 20-40 nM against certain specific tumor lines. One of these compounds (sudemycin D6) is currently in pre-clinical development with clinical trials planned for sometime in the next three years. We have also published our work on the synthesis of active analogs of pladienolide and herboxidiene. Very recently we have also developed a cell based high-throughput assay for the identification of compounds that induce the same splicing changes as the sudemycins, pladienolide analogs and herboxidiene. This cell line can also be used for in vivo pharmacodynamics, since the cells are luminescent only when acted on by these highly specific pre-mRNA splicing agents.
We have used this cell line in assay format to screen a library of known drugs and bioactive compounds to identify additional small drug-like molecules that also specifically induce the same splicing changes in tumors through an unknown mechanism that is actively being explored. Hits from this screen were used to design probes that we propose to use to identify the splicing modulatory target of these compounds by the preparation of an active biotin labeled probe.
Our hypothesis is that these hits can be used to design a new class of anticancer splicing modulators. The overall long-term goal is the development of several new classes of drug leads for the treatment of human cancers that are most vulnerable to spliceosome modulation, as well as the development of a better understanding of spliceosome function.
To develop a series of new drugs in this area, we are developing additional new lead compounds capable of potent spliceosome modulation in vivo and related useful biomarkers. We plan to accomplish this through exploration of the effects of our current active compounds on alternate splicing (AS) in tumors and through the refinement of our new spliceosome modulators via multiple iterations of synthesis and in vitro testing of carefully designed new analogs, followed by several experimental cycles involving detailed investigations of the pharmacology of our lead compounds.
About the Image
Hypothetical pharmacophore features for herboxidiene. Indicated features include F1, Donor (Don) and acceptor (Acc); F2, Acc; F3, Hydrophobic (Hyd); F4, Acc (epoxide); F5, Acc; and F6, Don and Acc. Figure Reference: Lagisetti C, Yermolina M, Sharma LK, Palacios G, Prigaro BJ and Webb TR. Pre-mRNA Splicing-Modulatory Pharmacophores: The Total Synthesis of Herboxidiene, a Pladienolide−Herboxidiene Hybrid Analog and Related Derivatives. ACS Chem. Biol. 2014, 9(3), 643–648.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA140474. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.