Dual-Action-Only PROTACs for Precision Targeting in Cancer

Presenter: Amelia Talluri

Faculty Sponsor: S. Thai Thayumanavan

School: UMass Amherst

Research Area: Cancer Studies

Session: Poster Session 6, 4:15 PM - 5:00 PM, Auditorium, A12

ABSTRACT

Proteolysis targeting chimera (PROTAC) based protein degraders has been a rapidly growing area of research, with a few PROTAC models in clinical trials for numerous diseases. These heterobifunctional molecules consist of two ligands connected by a chemical linker with one ligand binding E3 ubiquitin ligase and the other a protein of interest, thus inducing a gain of function pharmacology when bound to both. However, despite their promise, many PROTACs exhibit off-target effects that can lead to unintended toxicity. This study investigates if modifying PROTAC can specifically target cancer cells while reducing toxicity to healthy cells. The hypothesis posits that modified PROTAC will be active only in cancer environments, requiring two specific stimuli for protein degradation, such as a Dual-Action-Only PROTAC (DAO-PROTAC). The methods include the design and synthesis of DAO-PROTAC followed by in-vitro biological assays to evaluate protein degradation and cell toxicity. Results showed that protein degradation only occurred in the presence of both stimuli; when only one stimulus was present, toxicity was observed due to one ligand becoming active and inhibiting its target. The results demonstrate the potential advantages of DAO-PROTAC in creating a specific targeted therapy for cancer and the need for further adjustments to eliminate the risk of free ligands causing harm to healthy cells.

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