If we had to pick a keyword for the targeted protein degradation (TPD) field over the past two years, "molecular glue" would be the undisputed winner. From Merck's $400 million upfront payment setting a new preclinical out-licensing record, to the VAV1 molecular glue licensing deal just finalized by Hinova Pharmaceuticals on November 5th, the BD (business development) heat in this track has been burning continuously from September straight into November.
This article is approximately 2,190 words, with a reading time of about 3 minutes.
Imagine that inside your cells resides a tireless "cleaning crew."
They tag damaged or expired proteins with a label called "ubiquitin," then send them to the "shredder" (the proteasome) for disposal. This mechanism is crucial for sustaining life, and its discoverers were awarded the 2004 Nobel Prize in Chemistry.
The official Nobel Prize press release included a vivid description: the ubiquitin tag attached to proteins about to be destroyed is a "kiss of death." Once tagged, proteins are sent to the proteasome to be "chopped into pieces and completely destroyed."
This system is precise, efficient, and has a key characteristic: it doesn't indiscriminately dismantle proteins—it only destroys those that have been tagged. Who decides whether a tag is applied, and to whom? A group of "tag dispensers" called E3 ubiquitin ligases. The human genome encodes hundreds of E3 enzymes, each responsible for recognizing a specific set of target proteins.
From mechanism to designability: A more elegant strategy
What molecular glues do is essentially "forge" a tag. Like a drop of glue, one end sticks to the E3 enzyme, and the other end sticks to a pathogenic protein that should have been degraded but somehow escaped the "garbage disposal." It forcibly brings the two together. The E3 enzyme is "tricked" into attaching a ubiquitin tag to the pathogenic protein, which is then sent to the proteasome for destruction.
The beauty of this mechanism lies in the fact that it doesn't require direct binding to the active site of the pathogenic protein. Traditional small-molecule drugs need to find a pocket on the protein surface that is deep enough and "druggable," whereas molecular glues only need to create a contact surface. This opens doors to a large number of targets previously considered "undruggable." This unique mechanism has successfully unlocked targets that appear smooth on the surface and lack traditional binding pockets—targets previously deemed "undruggable" (accounting for 80% of the human proteome)—bringing them within the realm of intervention. 【1】
However, what has truly brought molecular glues out of the narrow confines of "thalidomide-class" compounds over the past two years is the systematization of discovery tools—work published in Nature in 2026 by Dana-Farber established a scalable screening platform for molecular glues and, for the first time, identified "metabolically activated" molecular glues, suggesting that molecular glue activity can be more tunable and context-dependent than previously thought.
Molecular glues: No longer a "niche track"
At the end of September this year, Merck acquired a preclinical molecular glue-type KRAS G12D inhibitor from Spurwing Therapeutics for a $400 million upfront payment, setting a new global record for upfront payments on a preclinical out-licensing deal, with a potential total consideration of up to $2.13 billion. 【2】
On October 9th, Roche entered into a platform-level collaboration with Ditto Biosciences around molecular glue degraders, attracted by its degrader screening system covering over 100 clinically relevant targets. 【3】
On November 5th, Hinova Pharmaceuticals and the US biopharmaceutical company Evommune jointly announced that the two parties had reached an exclusive licensing agreement for HP570, a highly potent and highly selective oral VAV1 molecular glue degrader with best-in-class potential, independently developed by Hinova using its targeted protein degradation technology platform. Evommune will pay Hinova a total upfront payment of $30 million; Hinova is also entitled to receive up to approximately $1.07 billion in potential development, regulatory, and commercialization milestone payments, as well as tiered royalties based on net sales in the licensed territory. 【4】
Putting these three deals together, there is a noteworthy phenomenon: assets and platforms are not in opposition. Assets are the output of platforms, and platforms are the source of assets—when an MNC is willing to pay a high upfront payment for a molecule that has not yet entered human trials, it is very likely also paying a price for the discovery capability behind the molecule—the ability to "reproducibly produce it."
According to statistics from a Soochow Securities research report, between 2023 and 2025, a total of 28 BD deals were reached in the global molecular glue field, with disclosed amounts exceeding $27 billion. Novartis, BMS, Gilead, AbbVie—almost all leading MNCs have placed their bets on this track. 【5】
For buyers, this is about pricing the ability to "reproducibly produce molecules." For early-stage investors, the difficulty lies in: what does this capability look like before the price is formed? In 2021, when Yifeng Capital participated in the Pre-A round financing of Biotheus, it faced exactly this question.
Efung's anchor point: 2021
In 2021, molecular glues were far from being a "hot trend" in China; discussion was far less than that of PROTACs, and it was nothing like today's hard currency in the BD market. What impressed Efung about Biotheus was not any single pipeline, but a platform that had been designed from the very beginning to be "intersecting."
Biotheus was incubated from ShanghaiTech University and founded in February 2020. Founder Dr. Yang Xiaobao has long been engaged in protein degrader R&D. The company's GlueTacs® platform simultaneously covers two routes: molecular glue degraders (GLUE) and bifunctional degraders (GLUETAC). 【6】
These two routes are not simply additive. Molecular glues have smaller molecular weights, while PROTACs are bifunctional molecules; the two have different emphases in terms of target types and druggability. Both routes share screening and validation systems, making the platform a "chassis" capable of continuously producing candidate molecules, rather than a one-off collection of assets. What Yifeng valued was this chassis designed as a platform from the start: its value does not depend on the success or failure of any single target, but on whether it can repeatedly produce new molecules.
Today, this chassis has verifiable progress. According to company disclosures, Biotheus has advanced three candidate drugs into clinical trials, with the core pipeline entering Phase II; on July 1, 2026, its globally first-in-class RSK bifunctional degrader GT818 received implied clinical trial approval from the Center for Drug Evaluation of the National Medical Products Administration. 【7】
The validation of this platform capability is not only reflected in clinical data. At the 2026 World Laureates Forum in November this year, Dr. Yang stated in an interview that "the cutting-edge discoveries shared by scientists at the WLA Forum provide support for the company's technology platform. The difference between this route and traditional chemotherapy—traditional chemotherapy drugs 'kill a thousand enemies but lose eight hundred of your own,' while protein degraders can directly eliminate pathogenic proteins in the body, representing an upgrade direction for drug R&D." 【8】
Conclusion
Today's heat around molecular glues is defined jointly by MNCs' massive checks and accumulating clinical progress. But beneath the heat, what is truly scarce is not capital, but teams capable of building underlying discovery capabilities before industry consensus forms. The value of Biotheus lies not in the fact that it happens to be standing on the protein degradation trend today, but in the fact that before the tide arrived, it had already built a platform capable of continuously producing molecules, and is now being tested step by step through clinical progress.
For early-stage investing, seeing the trend is certainly important, but what is harder is identifying, in a stage full of uncertainty, those underlying chassis with "repeatable validation capability." As for how much fruit this judgment will ultimately bear, that still needs to be answered by time and clinical data.
Data sources:
1、
https://mp.weixin.qq.com/s/RrJV7dCXKdPdhWn1wkLyBw
2、
https://mp.weixin.qq.com/s/4U6Npw0kgvMLm2Vo-fE_Lg
3、
https://mp.weixin.qq.com/s/4mb0hNYUdriQ3PCahZiDXw
4、
https://mp.weixin.qq.com/s/gldW8OVExjM7wIbiava2og
5、
https://mp.weixin.qq.com/s/jA6gnxRUjNSAL46bqVl9GQ
6、
https://mp.weixin.qq.com/s/IFB3sA-7CzUIBg2utm6xXQ
7、
https://mp.weixin.qq.com/s/Dr6hqXxHlnUGkScTtwiVEg
8、
https://baijiahao.baidu.com/s?id=1880747758834386212&wfr=spider&for=pc
We welcome your recommendations for cutting-edge biopharma topics to follow!
Which area's progress are you most interested in?
Feel free to share your views in the comments section.
【Disclaimer】
The content of this article represents only the views of the Company based on current public information and materials provided by portfolio companies, and does not constitute any investment advice, medical advice, or guarantee of the performance of any specific enterprise. Investing carries risks; proceed with caution. Readers should make independent judgments based on public information. Unauthorized reproduction or use for commercial purposes is prohibited.