The AE profile was similar to that reported previously, with a slightly higher incidence of atrial fibrillation. However, the low RBC-TI rate suggests insufficient efficacy of H3B-8800 at the dose levels tested. Further exploration of dosing schedules is warranted.

Moreover, E7107 had the greatest effect on intron retention. This study indicates/suggests that mutated SF3B1 UM cells are more sensitive to the splicing inhibitor E7107 than wild-type SF3B1 UM cells.

P1, N=127, Terminated, Hemavant Sciences GmbH | N=200 --> 127 | Trial completion date: Dec 2024 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Feb 2024; The study was terminated after conducting an interim analysis of the available data where it became evident that the observed efficacy results were not in alignment with the initially set expectations.

Here, we showed that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing factor 3B subunit 1 (SF3B1) H3B-8800 and E-7107...Furthermore, we demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators not only resulted in impaired DNA damage response and accumulation of DNA damage, but it sensitized cells to subsequent killing by poly(ADP-ribose) polymerase (PARP) inhibitors and chemotherapy and led to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML.

Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.

In conclusion, we developed a precise gene editing strategy of human HSCs to identify prexasertib as a promising therapy for SF3B1m myeloid neoplasms, and implicate the mitotic function of CHK1 as a SF3B1m sensitivity. The safety and toxicity profiles displayed in early phase clinical trials make prexasertib a suitable agent for further clinical investigation in SF3B1m MDS and its advanced stages.

Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in SF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards SF3B1-mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.

We designed and synthesized novel 4-acetoxypentanamide derivatives of spliceostatin A, whose 4-acetoxypentenamide moiety is reduced (7), isomerized (8), or substituted with methyl at the α-position (9). The results of biological evaluation against AR-V7 and the docking analysis of each derivative suggest that the geometry of the 4-acetoxypentenamide moiety of spliceostatin A is important for its biological activity.

Pre-treatment of cohesin-mutant cells with H3B-8800 for 3 days increased their sensitivity to the PARP inhibitor talazoparib 10-fold, while the sensitivity of wild-type cells to talazoparib was unaffected (Figure 1A)...In addition to talazoparib, we demonstrated significantly improved overall survival of STAG2-mutant AML PDX mice receiving sequential treatment of E-7107 and standard induction chemotherapy (doxorubicin and cytarabine), further expanding this strategy beyond PARP inhibitors...In summary, our study identifies a critical connection between cohesin mutations and splicing modulation in AML, creating a novel therapeutic strategy for these patients with very limited treatment options and poor outcomes. Our findings not only expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/sAML but we also propose this as a broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.

Moreover, IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures, and these results might be explained by the statistically significant increase in hENT1 expression (P < 0.05 vs. untreated control cells), potentially reversing PDAC chemoresistance. These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.

We further demonstrate that clinically used SF3B1 inhibitors synergize with CHEK2 inhibitors and chemotherapeutic drugs to block leukemia growth. Our study provides the proof of principle for posttranslational regulation of splicing components and associated roles and therapeutic implications for the U2 complex in T cell leukemia.