Department of Chemistry - PhD Student Seminar - Drug Design and Clinical Translation of PROTACs: Lessons from the First FDA-Approved PROTAC Medicine, Vepdegestrant (ARV-471 / Veppanu)

Student: Mr. Jingxian LI

Department: Department of Chemistry, HKUST

Supervisor: Prof. Yong HUANG

Abstract

Proteolysis Targeting Chimeras (PROTACs) have emerged as a groundbreaking modality in modern drug design, offering a novel mechanism to eliminate pathogenic proteins by hijacking the cell’s ubiquitin-proteasome system. Unlike conventional inhibitors that merely block protein function, PROTACs induce targeted degradation, providing new opportunities to address previously “undruggable” targets and overcome drug resistance.

This 45-minute seminar will follow a structured exploration of PROTAC drug design. It will begin with an introduction to the technology and its historical development, followed by the fundamental principles of PROTAC mechanism and molecular design — including target ligands, E3 ligase recruiters, and the critical role of linkers in forming productive ternary complexes. The core of the presentation will focus on a detailed case study of vepdegestrant (Veppanu, ARV-471), the first PROTAC to receive FDA approval on May 1, 2026, for the treatment of ESR1-mutated, ER+/HER2- advanced or metastatic breast cancer. The discussion will highlight its medicinal chemistry optimization, mechanism of action as an oral CRBN-recruiting estrogen receptor degrader, key clinical data, and design lessons learned.

The seminar will conclude by addressing major challenges in PROTAC development (such as pharmacokinetics, selectivity, and manufacturing) and future directions for expanding this technology beyond oncology. Designed to be informative for students and researchers in medicinal chemistry, pharmacology, and related fields, this talk aims to provide both foundational knowledge and insights into the clinical translation of targeted protein degradation.