pladienolide-b and Leukemia--Lymphocytic--Chronic--B-Cell

Small-molecule splice modulators have recently been recognized for their clinical potential for diverse cancers. This, combined with their use as tools to study the importance of splice-regulated events and their association with disease, continues to fuel the discovery of new splice modulators. One of the key challenges found in the current class of materials arises from their instability, where rapid metabolic degradation can lead to off-target responses. We now describe the preparation of bench-stable splice modulators by adapting carbohydrate motifs as a central scaffold to provide rapid access to potent splice modulators.

Topics: Alternative Splicing; Antineoplastic Agents; Carbohydrates; Drug Screening Assays, Antitumor; Epoxy Compounds; Fatty Alcohols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Macrolides; Models, Molecular; Pyrans; Spliceosomes

RNA splicing plays a fundamental role in human biology. Its relevance in cancer is rapidly emerging as demonstrated by spliceosome mutations that determine the prognosis of patients with hematologic malignancies. We report studies using FD-895 and pladienolide-B in primary leukemia cells derived from patients with chronic lymphocytic leukemia and leukemia-lymphoma cell lines. We found that FD-895 and pladienolide-B induce an early pattern of mRNA intron retention - spliceosome modulation. This process was associated with apoptosis preferentially in cancer cells as compared to normal lymphocytes. The pro-apoptotic activity of these compounds was observed regardless of poor prognostic factors such as Del(17p), TP53 or SF3B1 mutations and was able to overcome the protective effect of culture conditions that resemble the tumor microenvironment. In addition, the activity of these compounds was observed not only in vitro but also in vivo using the A20 lymphoma murine model. Overall, these findings give evidence for the first time that spliceosome modulation is a valid target in chronic lymphocytic leukemia and provide an additional rationale for the development of spliceosome modulators for cancer therapy.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Epoxy Compounds; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Macrolides; Mice; Mice, Inbred BALB C; Mutation; Phosphoproteins; Ribonucleoprotein, U2 Small Nuclear; RNA Splicing; RNA Splicing Factors; RNA, Messenger; Spliceosomes; Survival Analysis; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays