Linked to disorders including intellectual disability143, thrombocytopenia with absent radii syndrome

Linked to disorders including intellectual disability143, thrombocytopenia with absent radii syndrome144 and muscular dystrophy145. Author buy BIRB796 Manuscript Author Manuscript Author Manuscript Author Manuscript Implications for therapy Given the crucial roles of specific alternatively spliced isoforms in cancer biology146,147, as well as the potentially increased sensitivity of cancers to global perturbation of splicing efficiency relative to normal cells148,149, pharmacological modulation of splicing may represent an important therapeutic strategy. Aglafoline Spliceosomal gene mutations that cause alteration or gain of function are mutually exclusive with one another and are always coexpressed with a wild-type allele, suggesting that cells bearing spliceosomal mutations may be unable to tolerate further perturbations in splicing, and could therefore be preferentially sensitive to pharmacological splicing inhibition. A number of compounds and oligonucleotides that can disrupt or modulate normal splicing catalysis or alter splice site recognition through distinct pathways have been identified. Several compounds with antitumor activity were identified through natural product screens prior to the discovery of spliceosomal gene mutations. Synthetic analogues with higher stability, solubility and activity were subsequently developed, including E7107, meayamycin, spliceostatin A, and sudemycins. Biochemical studies identified SF3B1 as the likely target of these drugs, consistent with the observation that mutations affecting the R1074 residue of SF3B1 confer resistance to pladienolide and E7107152,153. Unfortunately, two separate Phase I clinical trials of E7107 revealed an unexpected and unexplained side effect of visual disturbances in 5% of subjects154,155. Further efforts are needed to determine whether this was an on- or off-target effect of U2 snRNP inhibition in vivo. In the meantime, several preclinical studies are evaluating the utility and safety of sudemycins156,157 for cancer therapy. Although the origin of splicing inhibitors’ general antitumor activities is unknown, two studies provided evidence that MYC expression renders cells sensitive to compounds that inhibit 3 splice site recognition148,149. More recently, Lee et al.158 reported that the splicing inhibitor E7107 reduced the leukemic burden and prolonged survival of mice carrying oncogene-driven myeloid leukemias if the leukemias had Srsf2 mutations, but not if the leukemias expressed only wild-type Srsf2. Lee et al. observed similarly specific targeting of patient-derived xenograft models of leukemias with spliceosomal mutations. These data suggest that splicing inhibitors such as E7107 are synthetically lethal with genetic lesions affecting the spliceosome. Interventions that target post-translational modification of splicing factors might also prove effective for therapy. For example, SR proteins are phosphorylated by kinases including topoisomerase I and members of the SR protein kinase and CDC2-like kinase families159161. These kinases affect SR protein subcellular localization and splicing activity162,163, exhibit altered expression and/or activity in cancer164,165, and can potentially PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19856273 act as oncogenes165. Small molecules that block activity of these kinases have been Nat Rev Cancer. Author manuscript; available in PMC 2016 November 03. Dvinge et al. Page 14 identified, including TG003, an inhibitor of CLK1 and CLK4, and SRPIN340, an SRPK1 and SRPK2 inhibitor that inhibits angiogenesis1.Linked to disorders including intellectual disability143, thrombocytopenia with absent radii syndrome144 and muscular dystrophy145. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Implications for therapy Given the crucial roles of specific alternatively spliced isoforms in cancer biology146,147, as well as the potentially increased sensitivity of cancers to global perturbation of splicing efficiency relative to normal cells148,149, pharmacological modulation of splicing may represent an important therapeutic strategy. Spliceosomal gene mutations that cause alteration or gain of function are mutually exclusive with one another and are always coexpressed with a wild-type allele, suggesting that cells bearing spliceosomal mutations may be unable to tolerate further perturbations in splicing, and could therefore be preferentially sensitive to pharmacological splicing inhibition. A number of compounds and oligonucleotides that can disrupt or modulate normal splicing catalysis or alter splice site recognition through distinct pathways have been identified. Several compounds with antitumor activity were identified through natural product screens prior to the discovery of spliceosomal gene mutations. Synthetic analogues with higher stability, solubility and activity were subsequently developed, including E7107, meayamycin, spliceostatin A, and sudemycins. Biochemical studies identified SF3B1 as the likely target of these drugs, consistent with the observation that mutations affecting the R1074 residue of SF3B1 confer resistance to pladienolide and E7107152,153. Unfortunately, two separate Phase I clinical trials of E7107 revealed an unexpected and unexplained side effect of visual disturbances in 5% of subjects154,155. Further efforts are needed to determine whether this was an on- or off-target effect of U2 snRNP inhibition in vivo. In the meantime, several preclinical studies are evaluating the utility and safety of sudemycins156,157 for cancer therapy. Although the origin of splicing inhibitors’ general antitumor activities is unknown, two studies provided evidence that MYC expression renders cells sensitive to compounds that inhibit 3 splice site recognition148,149. More recently, Lee et al.158 reported that the splicing inhibitor E7107 reduced the leukemic burden and prolonged survival of mice carrying oncogene-driven myeloid leukemias if the leukemias had Srsf2 mutations, but not if the leukemias expressed only wild-type Srsf2. Lee et al. observed similarly specific targeting of patient-derived xenograft models of leukemias with spliceosomal mutations. These data suggest that splicing inhibitors such as E7107 are synthetically lethal with genetic lesions affecting the spliceosome. Interventions that target post-translational modification of splicing factors might also prove effective for therapy. For example, SR proteins are phosphorylated by kinases including topoisomerase I and members of the SR protein kinase and CDC2-like kinase families159161. These kinases affect SR protein subcellular localization and splicing activity162,163, exhibit altered expression and/or activity in cancer164,165, and can potentially PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19856273 act as oncogenes165. Small molecules that block activity of these kinases have been Nat Rev Cancer. Author manuscript; available in PMC 2016 November 03. Dvinge et al. Page 14 identified, including TG003, an inhibitor of CLK1 and CLK4, and SRPIN340, an SRPK1 and SRPK2 inhibitor that inhibits angiogenesis1.