Edgar Torres
BME PhD Proposal Presentation

Date: 2026-11-09
Time: 2:00 PM - 4:00 PM
Location / Meeting Link: N357 HSRB II / https://emory.zoom.us/j/95944145067

Committee Members:
Khalid Salaita, PhD Simone Douglas-Green, PhD Felipe Quiroz, PhD Yonggang Ke, PhD Jean Koff, MD


Title: Design and development of amino acid-linked PROTACs for targeted protein degradation

Abstract:
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia characterized by the accumulation of malignant B lymphocytes. Bruton's tyrosine kinase (BTK) is central to B-cell receptor signaling and is therefore an important therapeutic target in CLL. Despite the revolutionary impact of BTK inhibitors on CLL therapy, acquired resistance and treatment related toxicities are still major problems. PROTACs represent an alternative approach to therapy in that rather than simply inhibiting the activity of a disease relevant protein they work by recruiting an E3 ubiquitin ligase to promote the degradation of that protein. The development of PROTACs as therapeutics has been hampered by a lack of understanding of the molecular determinants that govern degradation, poor drug like properties and a lack of cellular selectivity. To overcome these limitations we have developed amino acid-linked PROTACs (AAL-TACs), a modular platform that incorporates a stereochemically defined amino acid linker between the target binding and E3 ligase binding ligands. This provides a platform for systematic variation of degrader structure and also provides a functionalizable chemical handle for targeted delivery. Our initial studies have shown that amino acid identity, stereochemistry and linker architecture all have a significant impact on BTK degradation with lead AAL-TACs achieving nanomolar potency. Both experimental and computational data suggest that the differences in degradation activity between stereoisomers are due to differences in ternary complex formation rather than simply differences in binary ligand affinity. The proposal aims to establish the molecular design principles that govern AAL-TAC mediated BTK degradation and to engineer delivery strategies that improve cellular selectivity. First, we will look at how the amino acid linker architecture affects target engagement, ternary complex formation and downstream CLL signaling. Second, we will develop AAL-TAC antibody conjugates that will utilize CD19 mediated recognition and internalization to deliver BTK degradation specifically to malignant B cells. Third, we will engineer AAL-TAC lipid nanodisc conjugates and assess how nanodisc architecture and SR-B1 interactions impact intracellular delivery and degradation activity. We will assess both delivery platforms for selective BTK degradation in relevant CLL models. By combining molecular engineering, chemical biology and targeted drug delivery we aim to establish a framework connecting degrader architecture to intracellular activity and cellular selectivity. The work has the potential to lead to more effective therapies for CLL and to provide broadly applicable design principles for targeted protein degradation.