UC Santa Cruz

The Chromosome Region of Maintenance 1 or CRM1 protein is the master regulator that handles the export of hundreds of proteins and RNA molecules from eukaryotic cell nuclei. The imbalance of highly regulated cellular pathways due to overexpression of CRM1 is a distinct characteristic in forms of cancer. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Previous work has clarified that CRM1 inhibition by LMB is through an irreversible covalent inhibition, while second-generation inhibitors were designed through a slowly reversible covalent inhibition, leading to compounds with greatly improved tolerability that are in Phase I/II clinical trials. Chemically, the mechanism of action can be attributed to the Michael Addition between a nucleophilic cysteine residue and an electrophilic inhibitor. The work in this dissertation demonstrates the predictability and tunable of the reversibility of CRM1 inhibition. In particular, third-generation CRM1 inhibitors were designed with specific electronic nature at the C-α position in order to increase the acidity of the α-proton and potentially enhance the reversible Michael Addition and deconjugation from CRM1. We anticipate that the computational and experimental methods described in this dissertation will improve understanding of the therapeutic target, CRM1, and can be applied to similar targets.