Modulating splicing with small molecular inhibitors of the spliceosome

Abstract

Small molecule inhibitors that target components of the spliceosome have great potential as tools to probe splicing mechanism and dissect splicing regulatory networks in cells. These compounds also hold promise as drug leads for diseases in which splicing regulation plays a critical role, including many cancers. Because the spliceosome is a complicated and dynamic macromolecular machine comprised of many RNA and protein components, a variety of compounds that interfere with different aspects of spliceosome assembly is needed to probe its function. By screening chemical libraries with high-throughput splicing assays, several labs have added to the collection of splicing inhibitors, although the mechanistic insight into splicing yielded from the initial compound hits is somewhat limited so far. In contrast, SF3B1 inhibitors stand out as a great example of what can be accomplished with small molecule tools. This group of compounds were first discovered as natural products that are cytotoxic to cancer cells, and then later shown to target the core spliceosome protein SF3B1. The inhibitors have since been used to uncover details of SF3B1 mechanism in the spliceosome and its impact on gene expression in cells. Continuing structure activity relationship analysis of the compounds is also making progress in identifying chemical features key to their function, which is critical in understanding the mechanism of SF3B1 inhibition. The knowledge is also important for the design of analogs with new and useful features for both splicing researchers and clinicians hoping to exploit splicing as pressure point to target in cancer therapy.

A Challenging Pie to Splice: Drugging the Spliceosome

“…Although a series of studies have produced materials with increased stability,[22, 53] often these compounds are significantly less effective at modulating RNA splicing. [24––28] As illustrated in the current SAR maps (Figure 5),[19] only a small number of analogues, such as 23 (Figure 6), have been identified that offer enhanced activity over their natural product counterparts.…”

Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures

“…Altogether, current findings represent only a starting point for fully understanding the mechanistic effects of recurrent splicing factor mutations. Future efforts to elucidate these possibilities would guide longer-term efforts to exploit the therapeutic potential of spliceosome inhibitors [90], as recently highlighted by the spliceosome-sensitivity of MYC-driven cancers [91–93]. …”

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

“…To date, spliceostatin A, meayamycin, and pladienolide B are part of a well-characterized group of small-molecule splicing inhibitors (for a recent review, see Effenberger et al, 2016). These compounds target a specific spliceosome component, the U2 snRNP SF3b complex, and were originally discovered as substances that inhibited the growth of human tumors (Nakajima et al, 1996).…”