Favored by Capital and Hot Among Pharma Companies, This Small-molecule Degradation Agent Company Has Great Potential

While many pharmaceutical companies are chasing targeted and immunotherapy therapeutic drugs, protein degradation therapy has also attracted the attention of more and more companies and has become another new direction in the field of new drug R&D. Recently, Plexium, an emerging biotechnology company, announced the completion of financing US$ 102 million to develop a new generation of targeted protein degradation (TPD) therapies. This round was led by BVF Partners and TCG X, with participation from new investors Softbank Vision Fund 2, RA Capital Management, Surveyor Capital (a subsidiary of Citadel), Pappas Capital and other existing investors. 

The funds generated this time will enable Plexium to accelerate its R&D projects toward the clinic practices, including a molecular glue that selectively degrades the IKZF2 transcription factor, as well as selective protein degradation agents for CDK2, SMARCA2 and other undisclosed high-value targets. 

PROTAC & small-molecule monovalent degradation agent 

In the human body, the overexpression of pathogenic proteins has become an important reason for the occurrence and development of diseases. Can we use special means to send these pathogenic proteins to the proteasomes for degradation, so as to treat diseases? The answer is yes, and the key point is how to make disease-causing proteins ubiquitinated. This series of processes all involve the well-known PROTAC technology. 

PROTAC (Proteolysis Targeting Chimera) is a bifunctional small molecule, which is composed of target protein ligands and E3 ubiquitin ligase ligands connected by Linker. It uses the ubiquitin-protease system to recognize, bind and degrade disease-related target proteins. One of the greatest advantages of PROTAC technology is that it changes the target from "undruggable" to "druggable". It has made progress in the fields of tumors and autoimmune diseases, and has shown great potential in overcoming the drug resistance. From the birth of the world's first PROTAC molecule in 2001 to the clinical trial of the first PROTAC drug ARV-110 in 2019, targeted protein degradation therapy has attracted high attention from academia, pharmaceutical and biotechnological industries. 

Compared with PROTAC technology, Plexium focuses on the development of single-functional molecules. Through the DELPhe platform, a series of small molecule monovalent protein degradants are identified. These small molecules can bind to target protein or E3 ubiquitin ligase alone, resulting in conformational deformation of the protein through adjusting the selective ubiquitination of E3 ligase, and will ultimately induce the degradation of pathogenic target proteins. 

At present, there are less than 20 small-molecule degradation agent companies entering the clinical research stage worldwide, and there is no approved small-molecule degradation agent drug on the market. In this emerging track, Plexium as a pipeline has not yet entered the clinical research stage. What is it that attracts the investment? 

Plexium's unique DELPhe platform 

Plexium focuses on the development of monovalent degradation agents. Its DELPhe platform is named after the DNA Encoding Library (DEL) and Phenotypic Screening (Phe). The key factor of the platform is miniaturization. It combines the screening breadth of the DEL with the screening depth in cell-based deep multiplexed phenotype, enabling high-throughput screening of DEL of small molecules ranging from picoliter to nanoliter volumes to identify novel small molecules that bind to E3 ubiquitin ligases. The small molecules can bind to the target protein or E3 ubiquitin ligase alone, resulting in a change in protein conformation and ultimately degrading the target protein. 

As a unique drug discovery engine, its advantage lies in the use of the DEL technology to rapidly synthesize and screen the DNA codes at a low cost, and extend the screening of the DEL to the cell-based functional detection. In addition, the platform is very suitable for the research of E3 ubiquitin ligase and adjusting the effect of E3 ubiquitin ligase activity on cell phenotype. It can be used to identify novel small molecules binding to E3 ligase, and optimize small molecules according to the specific activity spectrum. 

Since DEL can analyze and screen millions of small molecules at one time, and screen the same E3 ubiquitin ligase in parallel for many times, the degradation small molecules screened by it can control and regulate the degradation mode of E3 ligase. 

Plexium's unique technical advantages 

Founded in 2017 as a biotech start-up, Plexium is headquartered in California. With the help of the DELPhe platform, Plexium has developed a comprehensive approach targeted protein degradation, enabling the discovery of a variety of targeted protein degradation modes, ranging from molecular glues to monovalent degradation agents. 

Plexium's R&D Pipelines (Image Source: Official website of Plexium) 

Plexium has a number of R&D pipelines, including a variety of molecular glues and molecular protein monovalent degradation agents, such as the molecular glue selectively degrading IKZF2 transcription factors, and the selective degradation agent for treating important proteins (CDK2 and SMARCA2). At the current stage, Plexium is exploring the molecular glue based on novel E3 ubiquitin ligase. 

Among them, IKZF2 transcription factor plays an important role in immuno-oncology signal transduction and is a potential cancer target. There is also a biopharmaceutical company (Gluetacs Therapeutics) in China that is developing a molecular glue degradation agent for IKZF2, which is still in the preclinical research stage. 

The other two targets, CDK2 and SMARCA2, are key factors regulating cell cycle and transcription activators respectively, and their degradation agents are used to treat HER2-/ER + breast cancer and NSCLC respectively. 

The screening of E3 ubiquitin ligase conjugates is a major technical barrier in the R&D of small molecule degradation agents. There are more than 600 kinds of E3 ubiquitin ligases in the human body, and each has its own tissue distribution characteristics, specific substrates, etc., but little is known about their druggability. Plexium's proprietary DELPhe platform has the potential to solve this problem. Through DEL screening, all E3 ubiquitin ligases can be potentially accessed, helping to discover novel E3 ubiquitin ligase regulating therapies, and discovering small molecules that can reduce the level of target proteins in cells using target-specific degradation determination and phenotype screening. 

Plexium has had multiple rounds of financing 

Financing Situation of Plexium (Image Source: CB Insights) 

Plexium has attracted the investment for many times, and multiple rounds of financing have been conducted since its establishment. 

In October 2019, Plexium announced the completion of the Series A financing of US$ 28 million. In January 2020, the company completed an additional financing of US$ 35 million (an extension of the Series A), bringing the total amount of Series A to US$ 63 million. With the completion of Series B, Plexium's total amount of financing has reached US$ 165 million.

In addition, on February 3, Plexium and Amgen signed an exclusive, global multi-year research collaboration and license agreement to identify novel targeted protein degradation therapies for challenging drug targets. 

Under the terms of the agreement, the collaboration will initially focus on two projects, with Amgen having the option to add additional projects. Plexium is eligible for receiving milestone payments based on R&D, regulation and commercial progress with the total amount of over US$ 500 million. Amgen owns the commercialization license for each project that is advancing to the scheduled preclinical development phase and will be responsible for global development and commercialization. 

Targeted protein degradation technology, which intervenes and regulates the process of diseases by changing protein homeostasis, is an important research field favored by pharmaceutical companies in recent years. We hope that with the progress of science and technology, more breakthroughs can be achieved in this new track to benefit the patients as soon as possible. 

References:

1. https://www.biospace.com/article/plexium-raises-102-million-to-advance-protein-degradation-pipeline-/;

2. https://www.plexium.com;

3. Plexium Announces $102m Financing to Advance Pipeline of Targeted Protein Degradation Therapies and Technology Platform. Retrieved February 23, 2022, from https://www.plexium.com/plexium-announces-102m-financing-to-advance-pipeline-of-targeted-protein-degradation-therapies-and-technology-platform/;

4. Plexium. Retrieved February 3, 2022, from https://www.plexium.com/platform-plexium-e3-ligase-drugs/.

About the Author:

Xiaobin

Xiaobin holds a Master's degree in Pharmacy and currently work as a public health control staff. Navigating through the intricate and complex data each day and feeling a sense of insignificance of herself. While being happy to witness the golden time of the development of Chinese bio-pharmaceutical industry. Hope to learn and improve together with everyone.