Since they were discovered around three decades ago, molecular glues have come a very long way as a therapeutic option for several different disease areas, including cancer and neurodegenerative disorders. Now, there are a rising number of molecular glue companies hoping to show clinical success with their candidates.
The term molecular glue refers to a small molecule that sticks two proteins together. The most common type links a target protein to an enzyme that causes the target to be broken down by the cell’s protein-degradation machinery.
Initially, the function of these small molecules was uncovered largely by chance. But, in recent years, scientists have managed to intentionally design them into a class of medicines, also called targeted protein degraders, to destroy disease-causing proteins. As a result, molecular glues are now seen as extremely promising solutions to potentially attack targets that were previously considered ‘undruggable.’
With the field of targeted protein degradation having expanded significantly in recent years, molecular glues have become the focus of several collaborations between small molecular glue startups and big pharma companies. In this article – listed in alphabetical order – we take a look at seven of the startups that are aiming to make it big with their molecular glues.
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Spun out of Dana-Farber Cancer Institute, C4 therapeutics is working in the area of targeted protein degradation to create a new generation of medicines that can help transform patients’ lives. With the help of its proprietary TORPEDO platform, the company has developed orally bioavailable small molecule degrader medicines that harness the body’s natural protein recycling system to rapidly degrade disease-causing proteins.
C4 Therapeutics’ platform allows it to uniquely design both molecular glues, which the company calls MonoDAC degraders, as well as heterobifunctional degraders, known as BiDAC degraders. According to the company, this means it has the capability to target almost any disease-causing protein, even ones that are considered to be undruggable.
In its pipeline, the company has a molecular glue called CFT7455. It is currently in a phase 1/2 clinical trial for the treatment of multiple myeloma and non-Hodgkin’s lymphomas. The molecular glue is designed to bind with high affinity to the E3 ligase adapter protein, Cereblon, in order to target and degrade IKZF1/3, which are transcription factors required for cancer cell growth and survival in multiple myeloma and non-Hodgkin’s lymphomas. In 2021, CFT7455 received an orphan drug designation from the U.S. Food and Drug Administration (FDA) for multiple myeloma.
Founded in April 2021 and based at JLABS @ Shanghai – an incubator of Johnson & Johnson – molecular glue company Degron Therapeutics is aiming to become a global leader in the discovery and development of small molecule molecular glue degrader drugs. It wants to use molecular glues to try and fix the unmet need whereby 80% of disease targets are considered undruggable by existing technologies.
Degron has a proprietary technology platform called GlueXplorer. Using this, the company employs three types of screening to find novel disease targets that can be degraded by molecular glues from the company’s compound library. Supported by established tools covering biochemical assays, cell-based assays, and mouse genetics, molecular glue degrader-target biology is then fully validated and moved towards preclinical and clinical development, to treat cancer, inflammation, metabolic diseases, and other diseases. Degron also predicts and selects potential molecular glue degrader targets by analysis of its in-house collection of chemical and target data, as well as directly screening its library for their specific degraders.
Last year, the company managed to raise $22 million in series A financing to help accelerate its growth and expand its GlueXplorer platform. Degron currently has three pipeline programs that have entered into the lead-optimization phase, including a first-in-class target with essential roles in a broad range of cancers and immune diseases.
Hoping to expand the scope of molecular glue drugs, Magnet Biomedicine emerged from stealth last month with a $50 million series A financing. Magnet is attempting to reimagine what is achievable with molecular glues by looking beyond known protein–protein interactions, and analyzing the broader protein landscape to pair target proteins with rationally selected presenter proteins to drive therapeutic effects.
The company takes a rational approach to discovering molecular glues, which, historically, have been found by chance. Its TrueGlue discovery platform combines state-of-the-art screening technologies using proprietary and diverse chemical libraries and human-biology-driven target selection to identify TrueGlues – the name given to the Magnet’s molecules.
These small molecules harness approaches beyond protein degradation and offer notable benefits such as restricting drug effects to disease-relevant tissues to avoid toxicities, inducing biological synergy on defined targets, mimicking monoclonal antibodies, and targeting historically undruggable proteins.
The company says that it wants to pioneer the discovery of novel molecular glue medicines for the treatment of cancer, cardiovascular disease, and immune disorders.
Monte Rosa Therapeutics
Based in the biotech hub of Boston, Monte Rosa Therapeutics’ says its mission is to reshape the disease treatment paradigms by discovering and developing a precision medicine-based portfolio of novel small molecule molecular glue degraders that selectively eliminate therapeutically relevant proteins in a broad range of indications with significant unmet medical need.
Monte Rosa’s proprietary Quantitative and Engineered Elimination of Neosubstances (QuEEN) platform is purpose-built to support the discovery and development of drugs that degrade therapeutically relevant proteins. The company’s lead candidate is MRT-2359, which induces the interaction between the E3 ubiquitin ligase component cereblon, and the translation termination factor GSPT1, leading to the targeted degradation of GSPT1 protein. The candidate is intended for the treatment of MYC-driven solid tumors, including lung cancer, as MYC transcription factors are well-defined drivers of human cancers. Last year, the first patient was dosed in a phase 1/2 clinical trial evaluating MRT-2359.
Just last week, Monte Rosa also announced that it had entered into a strategic collaboration and licensing agreement with Roche, to discover and develop molecular glue degraders against targets in cancer and neurological diseases previously considered impossible to drug. Under the agreement, Monte Rosa will receive an upfront payment of $50 million, and is eligible to receive future preclinical, clinical, commercial, and sales milestone payments that could exceed $2 billion.
Founded in 2015, Orionis has since developed its proprietary technology platforms and grown a deep pipeline of candidates. It has two platforms: one called A-Kine, which engineers target-selective, conditionally active cytokines designed to trigger anti-tumor immune responses, and one called Allo-Glue, which harnesses a first-in-class, genome-scale approach to discovery and rational design of molecular glues in order to reach previously intractable targets.
Its molecular glue platform uses multiple unique approaches to discover drug-like small molecules against disease targets that have remained elusive to traditional discovery approaches. The platform integrates a suite of proprietary chemical biology technologies, including biological assays, computational analyses, chemical libraries, and automated processes for high throughput discovery, rational design, and optimization of small molecules that promote or induce interactions of proteins in living cells. This includes molecular glues that can promote interactions leading to either target degradation or modulation of target function.
Last month, the company announced a multi-year collaboration with Genentech to discover novel small molecule medicines for challenging targets in major disease areas, including oncology and neurodegeneration. Under the terms of the agreement, Orionis will receive an upfront payment of $47 million, and will be responsible for the discovery and optimization of molecular glues for Genentech’s designated targets, while Genentech will be responsible for subsequent later-stage preclinical, clinical development, regulatory filing, and commercialization of such small molecules.
Based in Vienna, a city with a booming life sciences sector, molecular glue company Proxygen has developed a highly versatile, proprietary discovery engine supporting the specific and unbiased identification of molecular glue degraders against difficult-to-drug or completely undruggable targets at large scale. The company says that it has generated expansive knowledge and data in the discovery and chemical optimization of degrader molecules, positioning it as a pioneer in this novel modality.
In fact, Proxygen has already signed three licensing deals with major drugmakers since December 2020, when the company entered into a collaboration and licensing agreement with Boehringer Ingelheim to enable the identification of molecular glue degraders against various oncogenic targets. Its second major deal then came in 2022, with Merck KGaA, who struck a $554 million deal with Proxygen to identify and develop molecular glue degraders for clinical research. And, just recently, Proxygen signed another licensing agreement with Merck & Co., garnering an undisclosed upfront payment, as well as a potential $2.55 billion in milestones.
In addition to its partnered programs, Proxygen’s internal pipeline is pushing toward the clinic. In an interview with BioSpace following the deal with Merck & Co., Proxygen chief executive officer (CEO), Bernd Boidol, said the company will strategically expand its current headcount of 30 to 40, with an emphasis on maintaining the company culture.
Last year, molecular glue startup Triana Biomedicines leaped out of stealth mode with $110 million in series A financing, with the funding being used to establish a best-in-class, scalable platform to discover and develop molecular glues. Its platform aims to generate products that stabilize pre-existing or create de novo interactions between two proteins and alter the fate or functionality of the disease target.
By pursuing both a target-first and rational approach to molecular glue discovery, Triana wants to develop products for a wide range of therapeutic applications. The company’s innovative platform enables the evaluation and prioritization of over 600 known E3 ubiquitin ligases and their disease-relevant targets, as well as the rapid exploration of diverse chemical space for the identification of molecular glue degraders.
The company is initially focusing on inducing or enhancing the degradation of high-profile cancer targets.
A promising time for molecular glue startups
The targeted protein degradation market size is poised to grow from $113.85 million in 2022, to $247.61 million by 2030. This estimate suggests that there is no better time for molecular glue startups to be taking advantage of the potential this field offers.
Most molecular glues are designed to stick a target protein to a ligase that triggers degradation, but, theoretically, glues could stick any two proteins together. This means that they hold enormous potential, and researchers could develop small-molecule drugs for any disease-causing proteins that can be glued, which could be transformative for the treatment of diseases with previously undruggable targets.
And, with several molecular glue candidates currently in – or heading toward – clinical trials, it might not be too long before molecular glue startups begin seeing enormous success within the targeted protein degradation space.