Chelsi E. Almodóvar Rivera, Pharmaceutical Sciences graduate student (Tang Research Group), will be defending her PhD research thesis:

Development of Novel Cereblon-Based E3 Ligase Ligand-Linker Libraries for Targeted Protein Degradation

Traditional drug discovery has focused on using small molecules to block the function of various proteins. However, almost 80% of the human proteome is considered “undruggable” due to the lack of a defined functional site for small molecules to bind. Proteolysis Targeting Chimeras (PROTACs) are a promising therapeutic strategy that do not require the binding to functional sites. PROTACs promote the degradation of protein targets selectively by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of the cereblon (CRBN) E3 ligase such as pomalidomide, thalidomide, or lenalidomide are the most frequently used due to their favorable pharmacological properties compared with others. Moreover, although PROTACs have been used for a variety of protein targets, the rapid optimization and SAR evaluation of PROTAC libraries still experience many challenges, including the time-consuming lengthy synthesis and purifications before biological screening. In the first chapter, recent progresses to address this issue are discussed.

Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. In the second chapter, we will present a recently published modular chemistry platform for the efficient attachment of various ortho, meta, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction. Accordingly, we employed these new chiral CRBN E3 ligase ligands to create a partial PROTAC library that was further converted into full PROTAC libraries for androgen receptor (AR) degradation using a Rapid-TAC platform. Our results showed significant degradation of AR with three hit degraders as analyzed with a HiBiT and antiproliferation assay.  In the third chapter, we will be discussing our efforts for generating a partial PROTAC library based on achiral CRBN E3 ligase ligands and a full PROTAC library for the degradation of the Bruton’s Tyrosine Kinase (BTK) using the Rapid-TAC strategy. Our initial BTK-HiBiT results suggest significant degradation of the BTK protein using nine BTK degraders with para and meta phenyl substitutions to the achiral CRBN E3 ligase ligand. Lastly, we will be presenting our prelimiary efforts in the development of a third-generation Rapid-TAC using a thiol-ene “click” chemistry.  Specificially, we worked on optimizing the reaction conditions that could be used for the fast creation and biological evalution of full PROTAC libraries for any protein of interest.

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