A Challenging Pie to Splice: Drugging the Spliceosome

Abstract

Since its discovery in 1977, the study of alternative RNA splicing has revealed a plethora of mechanisms that had never before been documented in nature. Understanding these transitions and their outcome at the level of the cell and organism has become one of the great frontiers of modern chemical biology. Until 2007, this field remained in the hands of RNA biologists. However, the recent identification of natural product and synthetic modulators of RNA splicing has opened new access to this field, allowing for the first time a chemical-based interrogation of RNA splicing processes. Simultaneously, we have begun to understand the vital importance of splicing in disease, which offers a new platform for molecular discovery and therapy. As with many natural systems, gaining clear mechanistic detail at the molecular level is key towards understanding the operation of any biological machine. This minireview presents recent lessons learned in this emerging field of RNA splicing chemistry and chemical biology.

Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

“…Small molecule inhibition of SF3B1 can selectively kill cSCC cells. There is an ongoing clinical trial for haematological malignancies involving systemic delivery of an SF3B1 inhibitor and additional SF3B inhibitors are candidates for testing in the clinic [ 28 ]. cSCC cell lines can also be more sensitive than normal skin cells to death induced by suppression of splicing factors other than SF3B1.…”

“…Several families of naturally occurring compounds with anti-tumour activity have been found to target the spliceosome through an interaction with this complex [ 16 , 18 ]. Synthetic analogues of these inhibitors have now been generated [ 21 , 27 , 28 ]. The splicing factor SF3B1 is one of seven subunits of the SF3B complex and it is thought to be a direct target for these compounds [ 29 – 31 ].…”

“…The SF3B inhibitor H3B-8800 has recently entered a phase 1 clinical trial involving oral delivery for patients with haematological malignancies (NCT02841540). Additional small molecule modulators of the SF3B complex are candidates for testing in clinical trials [ 28 ].…”

An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

“…(Brooks, Choi et al 2014, Dvinge, Kim et al 2016, Obeng, Chappell et al 2016 In parallel to these recent discoveries, there has been a proportional upsurge in interest in the potential application of several recently discovered small molecule modulators of pre-mRNA splicing to cancer chemotherapy. (Lee and Abdel-Wahab 2016, Leon, Kashyap et al 2017) This effort has resulted in two Phase I clinical studies, and advanced pre-clinical development, for a series of ligands of the SF3B1 spliceosomal protein. These innovative drugs include a derivative of the natural product pladienolide (E7107), (Kotake, Sagane et al 2007) a synthetic analog of pladienolide (Mizui, Sakai et al 2004, Sakai, Sameshima et al 2004) (H3B-8800), (Seiler, Yoshimi et al 2018) and sudemycin D6 (SD6) (Lagisetti, Palacios et al 2013) a simplified synthetic analog of a natural product 464).…”

Alternative Splicing in the Hippo Pathway—Implications for Disease and Potential Therapeutic Targets

“…Aberrant AS is a major contributor to several neurological diseases including Duchenne muscular dystrophy (DMD) [ 15 ], spinal muscular atrophy (SMA) [ 16 ], diabetes [ 17 ] and is implicated in the development and progression of many types of cancer [ 18 , 19 ]. As such, there has been a lot of interest in using splice isoforms as disease biomarkers and in developing novel therapeutic strategies aimed at oncogenic splice isoforms [ 20 , 21 ].…”