UC San Diego

Since its discovery in 1977, the study of alternative RNA splicing has led to its implication as a major factor in the onset of disease. The recent identification of natural product and synthetic modulators of RNA splicing has opened access for a chemical-based interrogation of RNA splicing processes and has provided a new platform for molecular discovery and therapy. While splice modulators have entered clinical trials, limited clinical efficacy in splicing factor mutation driven malignancies, such as acute myeloid leukemia, has remained a challenge. There is a pressing unmet medical need for developing potent small molecule splice modulators (SPLMs) for the treatment of a broad array of malignancies characterized by splicing deregulation. However, the inability to practically access gram scale lead molecules with viable pharmacological properties continues to hinder their application. The dissertation herein details two projects that addresses these issues: 1. A scalable approach to prepare 17S-FD-895, a potent in vivo active splice modulator, that not only provided material to enable clinical translation but also furthered lead validation by expanding the structure-activity relationships that guide splice modulation. 2. Utilizing established synthetic methods and RNA isolation strategies to develop and profile a suite of splice modulator analogues to expand the structure-activity relationships of SPLMs and to gain a clearer understanding of the mechanisms underlying inherent gene selectivity in splicing.