Title:
High‑Throughput/High‑Content Screening (HTS/HCS)–Based Identification of Monovalent Degraders of the Immunomodulatory Enzyme IDO1 and Pathway Modulators
Abstract:
Targeted protein degradation (TPD) modulates protein function beyond inhibiting catalytic activity or protein–protein interactions. We designed pseudo‑natural products derived from (–)-myrtanol, termed iDegs. Through high‑throughput screening (HTS), we identified that iDegs both inhibit and induce degradation of the immunomodulatory enzyme indoleamine 2,3‑dioxygenase 1 (IDO1) via a distinct mechanism. iDegs enhance IDO1 ubiquitination and proteasomal turnover through the cullin–RING E3 ligase CRL2KLHDC3, which we demonstrate natively mediates IDO1 degradation. Thus, iDegs accelerate IDO1 clearance by engaging its endogenous proteolytic pathway. Unlike clinically explored IDO1 inhibitors, iDegs lower kynurenine production through dual action, enzyme inhibition and induced degradation, and thereby also modulate non‑enzymatic functions of IDO1. This unique mechanism of action opens therapeutic opportunities in oncology beyond classical IDO1 inhibition. In parallel, we encoded terpenes into alkaloids and profiled their biological activities using a Cell Painting assay, leading to the identification of inhibitors of Hedgehog signaling, modulators of ER stress.
About the speaker:
Xiu-Fen Cheng‘s research focuses on molecular innovation through the recombination of natural product fragments, integrating multidimensional approaches to systematically identify novel small-molecule degraders and elucidate their mechanisms of action. In parallel, she maps and analyzes the chemical space of small-molecule libraries involved in biological processes with the goal of screening and evaluating small-molecule modulators with potential druggability.
报告时间地点：
时间：2025/12/24 15:30-16:30
地点：#腾讯会议：165-346-193
