Harvard Medical School Researcher Dr. Liu Miao Advances Miniaturized PROTAC Degraders to Overcome Drug Development Challenges in Liver Cancer

Liver cancer is a common malignant tumor of the digestive system worldwide. According to the "Global Cancer Statistics 2020 (GLOBOCAN)" released by the International Agency for Research on Cancer (IARC) of the World Health Organization, more than 900,000 new cases of liver cancer were diagnosed globally in 2020, and more than 830,000 people died from liver cancer, with the number of deaths approaching the number of new cases.

Nearly half of these cases occur in China. The World Health Organization (WHO) estimates that 10 million Chinese people may die from liver cancer between 2015 and 2030. In 2021 alone, well-known actor Wu Mengda and musician Zhao Yingjun both passed away due to liver cancer. Previously, figures such as Jiao Yulu, revered as “the people’s good party secretary,” writers Lu Yao and Wei Wei, actors Fu Biao and Shi Shengjie, and singer Zang Tianshuo also lost their lives to this disease. In China, liver cancer has become a malignant condition that seriously threatens the health of people across all social strata. Consequently, it is often referred to as the dreaded “Chinese Cancer.”

This disease is extremely difficult to screen for and diagnose at an early stage; it is often detected only in the advanced stages. Existing drugs demonstrate low efficacy and significant side effects, making it challenging to achieve effective control. For instance, sorafenib, the only first-line targeted therapy for liver cancer, has an overall response rate of approximately 5%, with a median survival benefit of only about three months among responders. Despite its patent having expired for many years, it still generates nearly RMB 700 million in annual sales in the Chinese market.

In the film *Dying to Survive*, many patients and their families went to great lengths to purchase the Indian anticancer drug “Gleevec.” In reality, numerous liver cancer patients and their families have similarly struggled to obtain the targeted liver cancer therapy “sorafenib.” Last year, due to disruptions in China–India transportation caused by the COVID-19 pandemic, the price of this drug—characterized by low efficacy and significant side effects—surged dramatically in China. This underscores the urgent patient need for the research, development, and production of highly effective and safe medications for liver cancer.

Dr. Liu Miao’s team at Harvard Medical School is developing a unique targeted degrader technology, which differs from the inhibitor-based mechanisms of existing targeted therapies. In the context of drug development for liver cancer targets, LB6, a novel small-molecule targeted degrader for liver cancer developed based on this technology, offers advantages such as low molecular weight, high efficacy, and superior safety. LB6 holds promise for significantly addressing the current scarcity of effective treatments for liver cancer patients in China.

VCBeat New Medicine: Currently, most innovations and R&D in biopharmaceuticals are based on inhibitor technologies. As an emerging technology, how did you come to focus on degrader technology and choose it as your area of deep specialization?

Dr. Liu Miao:During my Ph.D. studies in medicine at the University of Tokyo, Japan, I primarily focused on the development of novel targeted therapies for the precision treatment of prostate cancer and bladder cancer.

After completing my Ph.D., I learned that Professor Daniel Tenen, a specialist in oncology at Harvard Medical School, is a leading authority in the field of solid tumor research. Intrigued by his team’s work on tumor-targeted degrader technologies, I applied to join his group. Perhaps due to our similar backgrounds—both of us having previously served as clinicians and having transformed our personal interests into professional careers—I was able to connect with Professor Tenen. Following several discussions, I successfully joined his project team at Harvard Medical School, where I gradually advanced from a junior researcher to a senior investigator.

After joining the team, we collaborated on several research and development projects focused on oncology drugs, particularly the development of novel protein-targeting degraders for solid tumors. Currently, the predominant technology for degrader drug development internationally is PROTAC (Proteolysis-Targeting Chimera). However, the resulting tripartite molecules tend to have high molecular weights, posing certain technical challenges in clinical translation. In contrast, our team is developing LB6, a novel small-molecule degrader for liver cancer, with a molecular weight below 500 Da. LB6 has demonstrated favorable efficacy and safety profiles, and the project is actively progressing through clinical translation.

VBInsight: Currently, who are the core members of your team?

Dr. Liu Miao:In addition to myself, the core team members include Radhakrishnan Sridhar, who holds a Ph.D. in medicinal chemistry, and Wang Zhaolin, who earned his Ph.D. in chemistry from Peking University.

From left to right: Dr. Liu Miao, Dr. Radhakrishnan Sridhar, and Dr. Wang Zhaolin

Dr. Sridhar was formerly a Senior Research Fellow at the Cancer Science Institute of Singapore, National University of Singapore, while Professor Daniel served as its Director. Thus, Dr. Sridhar and I share the same academic mentorship lineage. Prior to joining our team, Dr. Sridhar accumulated extensive industry experience in the field of PROTAC degraders, contributing to the synthesis of over one hundred drug candidates. In 2016, I began collaborating with Dr. Sridhar on the development of small-molecule degraders for liver cancer, and he is one of the key inventors of LB6.

During the clinical translation of projects developed by the team, compliance with GMP and GLP standards is also required. This area is primarily overseen by Dr. Zhaolin Wang. Dr. Wang has held key positions at major companies such as Biogen and has participated in multiple translational projects for small-molecule and peptide drugs from preclinical to clinical stages. He brings 25 years of experience in GMP and GLP within the U.S. pharmaceutical industry.

VCBeat New Medicine: Why Do Teams Choose Undruggable Targets for Drug Development?

Dr. Liu Miao:Historically, due to technological limitations, tumors were often treated with radiotherapy and chemotherapy. While these modalities exert cytotoxic effects on tumors, their non-selective nature also damages patients' healthy tissues. Many patients discontinue treatment due to intolerance of side effects, leading to severe disease recurrence.

Consequently, targeted therapies have emerged, designed to precisely inhibit specific tumor targets for disease treatment. However, currently only about 10% of these targets have been successfully developed into targeted drugs for clinical use. Another approximately 10% are under development. The remaining roughly 80% are considered “undruggable” targets given current inhibitor drug discovery technologies, meaning they cannot be developed into targeted inhibitory agents.

For the 20% of targets that are druggable, the annual market for inhibitor-based targeted therapies reaches $200 billion. If the remaining 80% of undruggable targets could be leveraged for drug development, the market potential would be immeasurable.To develop drugs targeting undruggable targets, it is essential to understand the stringent requirements for inhibitor drug development and the key pain points that need to be addressed.

First, inhibitor drugs must exhibit strong binding affinity to their targets and demonstrate biological activity. Furthermore, because tumors possess intrinsic adaptive mechanisms, therapeutic strategies that rely on inhibiting these original tumor pathways are prone to inducing drug resistance. On the other hand, although targeted inhibitor therapies offer precision treatment, a subset of these agents still carries significant toxicity and adverse effects.

How to Overcome the Pain Points of Targeted Inhibitor Drugs and Develop Therapeutics Against Undruggable Targets? Developing Degradation-Based Drugs May Be a Viable Path. Taking the Development of Targeted Degraders for Liver Cancer as an Example: The Association Between the SALL Target and Liver Cancer Has Long Been Established in the Scientific Community. However, due to the highly complex protein structure of SALL, conventional small molecules struggle to achieve strong binding affinity, thereby hindering effective targeting. Even if binding occurs, it remains difficult to ensure whether the resulting complex retains biological activity.

However, by leveraging degrader technology to “degrade” rather than “inhibit” the target, the drug does not need to exert biological activity, and only moderate or higher binding affinity to the target is required for the development of corresponding degradative drugs.Because many degrader technologies exert therapeutic effects by activating the intracellular ubiquitination system, thereby leading to degradation of target proteins by intracellular proteases. Drugs developed based on this technology also offer advantages such as minimal side effects, high efficacy, and a low propensity for drug resistance.

Arterial New Medicine: Compared with the PROTAC technology, which has gained significant traction in recent years, what breakthroughs has your team achieved in developing next-generation degrader technologies?

Dr. Liu Miao:Current PROTAC drug structures resemble a dumbbell, featuring a “tripartite structure” composed of three small molecules: one end consists of a ligand small molecule that binds to the target protein, the other end comprises a ligand that recruits the E3 ubiquitin ligase system, and the two are connected by a linker. The E3 ubiquitin ligase system functions as an intracellular “waste clearance” mechanism; it has its own substrates, with different E3 ubiquitin ligases ubiquitinating distinct proteins. Owing to this specificity, the tripartite structure can be paired with different E3 ubiquitin ligases to achieve targeted degradation of specific proteins.

However, there are still areas for improvement in PROTAC design. First, although PROTACs consist of three small molecules, their overall molecular weight is relatively high (typically >1,000 Da), resulting in poor cell membrane permeability. Second, the structural stability of this linker-connected tripartite molecule cannot be guaranteed, potentially leading to off-target effects and reduced efficacy.

Therefore, this molecular structure is somewhat “anomalous.” If you classify PROTACs as large molecules, they are in fact composed of three small-molecule compounds; however, their high molecular weight precludes classification as small molecules. Determining the appropriate analytical standards for such entities poses a significant challenge in clinical translation.

Currently, there is a deluge of publications on drug development leveraging PROTAC technology. While it represents a promising research hotspot for overcoming the challenges of targeting previously "undruggable" proteins, significant barriers related to druggability remain to be addressed. Our team is making steady efforts to overcome these hurdles.

Some teams have adopted a molecular glue development strategy, utilizing small molecules to reduce the molecular weight of degraders, which can also modulate ubiquitination efficiency and facilitate target degradation. However, molecular glue technology lacks precise programmability; each molecular glue can only promote degradation of its specific substrate by engaging the corresponding E3 ubiquitin ligase pathway.

After extensive exploration and accumulation, our team has developed a degrader drug with a molecular weight compressed to the range of 300–500 Da. This innovation transforms the traditional tripartite structure into a simple monomeric small-molecule architecture featuring dual functionalities: target binding and E3 ubiquitin ligase recruitment. This monomeric small molecule not only facilitates the degradation of target proteins but also retains the low molecular weight characteristics typical of molecular glues, thereby overcoming the inherent limitations of conventional tripartite structures in terms of structural stability, efficacy, and cell membrane permeability. Furthermore, this small molecule is a novel structure developed through de novo synthetic design rather than compound screening, thus avoiding issues such as patent overlap.

We recognize that the miniaturization of PROTACs/degraders is a key direction for future research and development in degrader technologies.

VCBeat New Medicine: Your team has currently established multiple technology platforms for novel protein degraders. Based on these platforms, why did you choose to first build a project pipeline targeting liver cancer?

Dr. Liu Miao:As a researcher with a clinical background, I have repeatedly confronted diseases that pose significant unmet clinical needs yet lack approved treatments. We frequently receive letters from patients and their families around the world, witnessing many individuals who, despite the absence of effective therapeutic options, continue to grasp at any last hope. All too often, by the time I read these messages and attempt to respond, contact has already been lost. It is deeply distressing to see that our research aligns precisely with patients’ symptoms, yet delays in development prevent timely access to potential benefits. This reality is a major reason behind our determination to accelerate the translation of our scientific achievements into clinical practice.

Among these, I have received numerous letters from liver cancer patients and their families in China. While liver cancer is considered a “rare” tumor abroad, it is often referred to as “China’s cancer” domestically due to its high prevalence. Despite the large patient population, sorafenib remains the only first-line targeted therapy approved for liver cancer. However, sorafenib has an efficacy rate of less than 5%, and even those “lucky patients” who respond gain only approximately three months of additional survival. Even so, the market for sorafenib remains substantial. Although new treatment options such as the combination of lenvatinib and PD-1 inhibitors have emerged, their effectiveness remains unsatisfactory, while the associated medical costs are prohibitively expensive.

For patients with advanced hepatocellular carcinoma who are insensitive to surgical intervention, there is a severe lack of drugs with both high efficacy and high safety. To address this unmet need, we have developed LB6, a novel small-molecule degrader for liver cancer targeting the tumor transcription factor SALL, an historically “undruggable” target. LB6 has a molecular weight of only 464 Da. Current preclinical data from animal models demonstrate that LB6 exhibits favorable safety, efficacy, and target specificity.

VCBeat: What major breakthroughs are expected for the LB6 project in the near term? Additionally, what other pipeline assets does the team have in its portfolio?

Dr. Liu Miao:The LB6 project is the fruit of multi-year collaboration among multiple teams. Currently, experimental data for the small-molecule degrader drug targeting liver cancer are comprehensive, and the related CRO studies are expected to be completed within one and a half years to support IND submissions to the CFDA/FDA.

In addition to the LB6 project pipeline, we are continuously developing new product pipelines and proprietary technologies based on our monomeric small-molecule degrader platform, peptide-induced PROTAC degradation platform, oligonucleotide-induced PROTAC technology platform, and clathrin-mediated lysosomal degradation platform. Currently, we have pipeline layouts targeting lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, and other indications.

Perhaps one day in the future, major diseases such as liver cancer and pancreatic cancer, which currently strike fear into our hearts, may truly be conquered through our efforts.