Page 238 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

PP-55

Discovery and development of STING inhibitors and molecular glue

degraders from marine natural products

4
1,4
Po-Hsun Lee, #,2,3 Wan-Chi Hsiao, Szu-Hsuan Chen, Guang-Hao Niu, Y u -Hsin
2,3
2
5
Chiu, Ping-Jyun Sung, Lun Kelvin Tsou,* Mingzi M. Zhang*
,3
,4

1 Graduate Program of Biotechnology in Medicine, NTHU & NHRI
2 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
3 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli,
Taiwan
4 Institute of Biotechnology and Pharmaceutical Research, National Health Research

Institutes, Miaoli, Taiwan
5 National Museum of Marine Biology and Aquarium, Pingtung, Taiwan
* E-mail: kelvintsou@nhri.edu.tw; zhangmz@nhri.edu.tw

Abstract
Conventional drug discovery was achieved by directly moderating target protein activity,
such as inhibitors. Recently, use of targeted protein degraders (TPDs) to degrade target proteins
by harnessing the cell's proteolytic machinery has emerged as a promising strategy for drug
development. There two main classes TPDs are proteolysis targeting chimeras (PROTACs) and
molecular glue degraders (MGDs). PROTACs are bivalent compounds composed of an E3
ligase recruiting ligand and a protein of interest (POI)-targeting warhead connected by a flexible
linker. In contrast, MGDs offer superior advantages in drug development. Notably, MGDs are
monovalent molecules usually with lower molecular weight, which is more favorable for oral
bioavailability. Nonetheless, MGDs relies on inducing protein-protein interactions, which are
often complex and not well-understood, greatly limiting de novo design of MGDs. Thus, to date
most MGDs are the result of serendipitous discoveries. Natural products derived from microbes,
plants and animals, are proven sources of therapeutic agents. Evolutionarily selected for
interactions with biomolecules, natural products provide the opportunity to bind undruggable
proteins at new or cryptic binding sites. We previously showed that excavatolide B (excB), a
potent anti-inflammatory briarane-type diterpenoid isolated from soft corals, is a new class of
covalent inhibitor targeting a key immune modulator - Stimulator of interferon genes (STING).
Given that overactive STING is the basis for many human diseases, including autoimmune
disorders, inflammatory bowel diseases and neurodegeneration, here we describe the
development of more potent briarane-type STING inhibitors with improved pharmacological
properties through late-stage diversification of the excB. Furthermore, we report the discovery
of briarane-type MGDs of STING.

Keywords: Soft corals; Excavatolide B (excB); STING; Molecular glue degraders (MGDs)