When Will the Protein Degradation Field Reach Its Inflection Point Over the Next Two Decades? — Insights from VB ThinkTank
2015 was a pivotal year for the field of protein degradation. The laboratories of Bradner, Ciulli, and Crews developed improved PROTAC molecules, propelling the technology to new heights. Around this time, pioneers in the PROTAC field founded several companies, including Arvinas, C4 Therapeutics, and Kymera Therapeutics. In China, nearly half of the protein degradation companies were established around 2018. After two decades of research accumulation, what is the current state of development in the protein degradation field, and what does the future hold?
On May 26, VCBeat New Medicine, in collaboration with Mefang Health Fund, invited Rannuo Biologics and Viva Biotech to host an online panel discussion series on “Protein Degraders,” aiming to explore the question: “How will protein degraders fuel innovation over the next two decades?”
▲ 【VB[Think Tank]-【Protein Degrader Series】
Front row (top), from left to right: Mr. Hu Hongdan, Executive Director of Mifang Health Fund; Wang Jiaqi, Senior Researcher at VCBeat Eggshell Research Institute
Second row (bottom), from left to right: Dr. Dai Han, Chief Innovation Officer & Head of the Innovation Center at WuXi Biologics; Dr. Ying Weiwen, Founder of Renuo Bio; Hao Han, Editor-in-Chief of VB New Medicine
Unlike traditional small-molecule inhibitors and antagonists, protein degrader technology has emerged as a powerful tool in new drug development due to its ability to induce the degradation of disease-causing target proteins. As an emerging technology, what is the current state of development for protein degraders? Three experts shared their respective perspectives.
Dr. Ying Weiwen, Founder of Rannuo BiotechDiscussed the differences between protein degradation technology and other drug development approaches: "The most critical distinction between protein degraders and traditional small-molecule drugs lies in the fact that,"Currently, the druggability of protein-degrading molecules remains a significant challenge., from the perspective of target selection and technology development, protein degraders are still developed based on medicinal chemistry. In terms of technological innovation,Protein degradation is considered capable of targeting previously undruggable targets., achieving effects similar to gene knockdown and knockout in gene therapy by degrading target proteins.”
Mr. Hu Hongdan, Executive Director of Mifang Health FundFrom an investor’s perspective, the development prospects of the protein degradation field were discussed: “First, protein degradation represents a novel therapeutic modality and mechanism of action within the pharmaceutical industry. In light of the central dogma, while gene editing primarily targets the DNA level and nucleic acid drugs focus on the RNA level, protein degraders directly regulate at the protein level by selectively degrading disease-causing proteins, rather than merely exerting the inhibitory effects characteristic of traditional small-molecule drugs. Second, protein-degrading drugs, including PROTACs, do not require high-affinity binding to their target proteins. These advantages significantly expand the range of druggable targets.”
“From the perspective of E3 ligases, current efforts are predominantly focused on CRBN and VHL ligands; however, approximately 600 other E3 ligases remain unexplored, indicating substantial potential for expansion in protein degradation at this level. In terms of degradation mechanisms, beyond PROTACs and molecular glues, emerging technologies such as LYTAC, AUTAC, and ATTEC are broadening the mechanistic scope of the protein degradation field. Furthermore, as protein degraders still fall within the small-molecule domain, drug development, regulatory approval processes, and supply chains are relatively mature. These factors collectively underscore that protein degradation is a highly strategic area for investment and development.”
Dr. Han Dai, Chief Innovation Officer & Head of the Innovation Center at WuXi Biologywhich outlines the current challenges that need to be overcome in protein degradation technology: “Although the advantage of PROTACs lies in targeting undruggable targets, in the early stages, researchers still focused on validated targets.The rationale is that, for novel molecular modalities, the industry prefers to initially develop them against relatively well-validated targets. This approach helps ensure that the molecular modality is undergoing continuous optimization; if issues arise, it becomes possible to determine whether they stem from the target or from the molecular modality itself. Due to the inherent physicochemical properties of protein-degrading molecules, their druggability has faced significant challenges in recent years. However, with accumulated experience, protein degradation-related technologies have improved substantially, spanning molecular design, prediction of physicochemical properties, and formulation studies. Therefore, we remain confident that this field holds considerable potential, as it opens up a new avenue, making it possible to address problems that traditional small-molecule drugs cannot solve.
Although the greatest advantage of protein degraders lies in their ability to target undruggable targets, at the current stage, many companies are still focusing on validated targets. Products from companies such as Arvinas, C4 Therapeutics, and Kymera primarily target already druggable targets like AR, BRD4, KRAS, and MDM2, rather than truly focusing on undruggable targets. Why is this the case?
Dr. Ying Wenwenmentioned,For an emerging field, startups need to find a balance between maturity and innovation.“Protein degradation technology is still in its early stages. Innovative biotech companies established in this field are primarily focused on building new technological platforms and are therefore less inclined to take excessive risks in target selection at the outset,”From a business model perspective, risk control must still be taken into account.However, we have observed that as the understanding of protein degradation has deepened, some companies have significantly expanded their target selection.
“Another key consideration is target selection. Rannuo Bio operates under the premise that many of its selected targets have available co-crystal structures. Since the binding modes between such targets and small-molecule ligands are well characterized, and their biological mechanisms are relatively well understood, this knowledge enables more rational design of degrader molecules. In-depth investigation of targets with co-crystal structures helps mitigate the risks associated with product development.”
Mr. Hu Hongdanthen broadens the focus to novel therapeutic mechanisms across the entire biopharmaceutical field. In his view,In addition to protein degraders, new mechanisms—including synthetic lethality—will undergo a process of first validating mature targets and then exploring breakthroughs with novel targets.“After the first wave of novel therapies emerged, validation was certainly conducted first through relatively mature targets. For instance, although the concept of synthetic lethality had been studied for a long time, it was not until around 2005 that PARP and BRCA were identified as a synthetic lethal gene pair, leading to the approval of PARP inhibitors as the first synthetic lethality-based clinical drugs. However, we can observe that even after the market launch of PARP inhibitors, which validated the synthetic lethality mechanism, most of the targets being pursued remain those traditionally considered ‘undruggable,’ such as p53, c-Myc, and RAS. We can see that,”The initial target selections following the emergence of new therapeutic mechanisms are typically well-established targets, with subsequent pipeline layouts becoming increasingly innovative.”
If 2015 marked a highlight in the development of the protein degradation field, then by calculation, this area is still in its early stages. Many people still regard protein degradation as an emerging technology. In the future, when will this industry reach its maturity, and when will it experience a breakthrough in development?
Dr. Ying Wenwenstated: “I have always believed that protein degradation is somewhat similar to ADC technology. The concept of ADCs was proposed in the 1970s, but it took 40 years for the field to truly explode. Based on the current development of the protein degradation sector, I expect it to enter a mature phase within the next 20 years. I believe that protein degradation still falls within the realm of small-molecule drugs; from a technical development perspective, its difficulty is slightly lower than that of ADCs, so I thinkThe protein degradation industry is highly likely to replicate the 40-year development cycle of antibody-drug conjugates (ADCs), and should usher in a golden age of explosive growth over the next decade.”
Dr. Han DaiIt is believed that there are two directions for the explosion point of protein degradation technology: "First is the innovative development of E3 ligase ligandsCurrently, many companies have already initiated the development of novel E3 ligase ligands. If researchers can identify suitable new ligands that exhibit disease-specific and tissue-specific targeting for E3 ubiquitin ligases, these ligands hold dual potential: firstly, they may themselves serve as candidates for drug development; secondly, their tissue distribution specificity can help widen the therapeutic window of related PROTACs for specific diseases.
“Another breakthrough point lies in historically undruggable targets“In the early stages, outstanding PROTAC companies like Arvinas primarily focused on targets with a certain degree of clinical validation. In reality, we are seeing an increasing number of companies beginning to develop PROTACs for undruggable targets. Protein degradation holds significant theoretical advantages in addressing undruggable targets. Although it is not a molecular modality capable of solving all problems in practical application, it can substantially lower the R&D barriers for difficult-to-drug targets. Therefore, I believe this field will experience a powerful surge in the future.”
As Arvinas’ products enter Phase II clinical trials, the druggability of protein degraders will be fully validated in the near future. Emerging degrader technologies have risen to prominence; although several key challenges remain to be addressed, they have significantly expanded the potential applications of degrader technology and may pave the way for novel therapies in the field of targeted protein degradation. We look forward to continued milestone advancements in this field in the years ahead.
For more information on the protein degrader industry, please scan the QR code below to add our assistant and join the [Protein Degrader] Industry Exchange Group.
