Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

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 also key to the pathology of numerous diseases, particularly 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 recently been characterized, some showing promise in preclinical studies. While the targets of most splicing modulators are constitutive RNA processing components, possibly leading to 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 potentially promising novel therapeutic strategy in cancer treatment. Here, we review their reported effects, mechanisms, and limitations. Alternatively spliced RNA isoforms and elevated RNA processing activity have been identified in different types of cancer, making RNA processing an attractive therapeutic target.Several small molecule RNA splicing modulators have been identified as part of intensive ongoing drug screening approaches.The observation of specificity of chemical splicing modulators for particular RNA isoforms has prompted the investigation of the mechanisms that confer splicing specificity.Molecular addiction to weakly spliced isoforms is a particularly attractive target for the development of chemical splicing modulators in cancer therapy.