UC Berkeley

Natural products have long been a rich source of medicinal compounds and inspirations for drug discovery. Among these, molecules that interact with their targets through covalent bonds are highly attractive in biological applications. This dissertation describes our studies on the biosynthetic relationship and chemical synthesis of potentially covalently acting natural products of gymnastatin family, as well as the application of the cysteine-targeting limonoid natural product nimbolide and triterpene derivative bardoxolone for targeted protein degradation.Gymnastatins are a family of cytotoxic natural products derived from tyrosine, which possess a variety of electrophilic functional groups. Through bio-inspired strategies, the total syntheses of gymnastatin G, dankastatin B and dankastatin C was achieved. The previously presumed biomimetic strategy failed to provide the desired stereochemistry during formation of the bicyclo[3.3.1]nonane core of gymnastatin G, complicating our understanding of the biosynthesis of gymnastatins. In addition, the connection between gymnastatin G and a related natural product aranorosin was established through a simple chemical transformation. These results provide further insight into the biosynthesis and chemical reactivity of gymnastatins (Chapter 1). In Chapter 2, we describe the use of nimbolide as a novel E3 ligase recruiter in targeted protein degradation (TPD) applications. While TPD and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities, the lack of E3 ligase recruiters remains one of the major limitations of current TPD strategies. Extending our recent discovery of nimbolide as a covalent recruiter for the E3 ligase RNF114, we show the broader utility of this E3 ligase recruitment by developing a nimbolide-based PROTAC BT1, which selectively degrades oncogenic fusion protein BCR-ABL over c-ABL in leukemia cancer cells. The selectivity profile of BT1 is opposite to existing cereblon or VHL-recruiting BCR-ABL degraders of similar linker composition. This work further establishes nimbolide as an additional general E3 ligase recruiter for use in PROTACs and demonstrates the importance of expanding the arsenal of E3 ligase recruiters. In Chapter 3, an unexplored mode of E3 ligase recruitment, namely, covalent, reversible E3 ligase recruitment was explored. Efficient proteasome-mediated degradation of BRD4 was achieved by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1, which further expanded the TPD toolbox to include bardoxolone as an easily prepared E3 ligase recruiter and further highlighted the power of natural products in such applications.