Are molecular glues the key to undruggable targets?

molecular glues

Molecular glues have been garnering the attention of big pharmas like Novo Nordisk lately, as the multinational giant inked a deal worth up to $1.46 billion with Neomorph, last month.

As more biopharmas get sticky with molecular glue developers and venture capital interest grows, we decided to review the field of molecular glues in this article.

Table of contents

    How do molecular glues work?

    A molecular glue is a type of molecule that enables protein-protein interactions. They act as a glue by boosting the affinity between proteins in cells. Benedict Cross, chief technology officer (CTO) at PhoreMost, explained that the term is used to describe an emerging and distinctive set of molecules that act via a very different mechanism to traditional drugs. By enhancing affinity between proteins, they exhibit a therapeutic effect.

    The most common type links a disease-causing target protein to an enzyme that causes the protein to be broken down by the cell’s protein-degradation machinery. This takes place when the glue binds to an enzyme called E3 ligase. When it binds to the enzyme, it changes the shape of the enzyme so that it can attach itself to the target protein more easily. Then, the enzyme adds a chain of proteins called ubiquitins to the target protein, which promotes protein degradation. As a result, the target protein is broken down.

    “This phenomenon has incredible potential, as it opens up immense new possibilities in drug development. Controlling protein and cell function through this ‘induced proximity’ approach is currently used across multiple therapeutic areas, and has already made an impact in the field of targeted protein degradation where development has been accelerating over recent years,” said Cross. 

    Similar to proteolysis targeting chimeric (PROTAC) molecules, molecular glues are designed to drug undruggable targets, both regarded as precision medicines. But unlike PROTACs, which consist of two regions that are connected via a linker, molecular glues are made up of a single part. 

    The challenge of discovering new molecular glues

    The most well-known molecular glue, thalidomide, was developed in the 1950s to treat morning sickness caused by pregnancy, but disastrously, it led to birth defects in thousands of children. The drug was then banned in several countries, and prompted countries to introduce tougher regulations for licensing drugs. While the drug was barred from treating morning sickness, it is currently used to control inflammation in patients with leprosy, and is a targeted cancer drug for treating myeloma by preventing the growth of blood vessels that aid in tumor growth.

    The term molecular glues was coined more than three decades ago, and its potential impact in treating diseases has been realized for a while now, however, developing them has proven to be quite challenging. This is because molecular glues are not only required to bind to a protein but also induce the target protein to stick to another protein.

    “There is currently no rational or systematic way to discover molecular glues. This represents a challenge that must be overcome if we are to realize the full potential of this modality. Each time a new molecule is serendipitously discovered, we learn more about the molecular glue’s mechanism of action, but the field really needs an innovative approach to derive new molecules that can become future drugs,” said Cross.

    Approved molecular glues

    Thalidomide and its analogs – lenalidomide and pomalidomide developed by Celgene and sold under the brand names Revlimid and Pomalyst – are among the only protein degraders that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of blood cancers. The immunosuppressants cyclosporine A, which was greenlit by the FDA back in 1983 to prevent organ rejection during transplants, as well as rapamcyin, are said to act as molecular glues

    Cyclosporine A, which is now sold under the brand name Sandimmune by Novartis, can induce protein–protein interplay, making it a molecular glue, although this revelation only came to light years after it was approved. The drug recently made news when the FDA pulled two batches of Sandimmune from the market after the oral solution formed crystals in the bottles. The FDA warned that this could result in underdosing or overdosing, both of which could have dangerous effects.

    On the other hand, rapamcyin has molecular glue-like binding properties as it forms a complex with a protein before attaching to an enzyme. The drug does so to block the protein mTOR. It is used in anticancer and rare disease therapies, and to prevent rejection during organ transplants.

    The recent trend in biopharma collaborations to develop molecular glues suggests that the industry may be onto something more promising. Novo Nordisk’s partnership with American biotech Neomorph aims to drug undruggable targets. Neomorph will lead discovery and preclinical studies, after which Novo is set to take on clinical development of the molecular glues, as well as commercialize the drugs. 

    More recently, Merck spent $16 million to partner with Massachusetts-based C4 Therapeutics to discover two protein degraders targeting cancer proteins – encoded by oncogenes. C4 will use its TORPEDO platform to design its molecular glues, which has already helped discover cancer drugs that are currently in the clinic to treat cancers like multiple myeloma and non-Hodgkin’s lymphoma. The biotech can rake in up to $740 million in milestone payments, according to the deal.

    Merck’s alliance with Austrian biotech Proxygen, worth up to $2.55 billion, is also centered on developing molecular glue degraders against multiple, undisclosed therapeutic targets. The deal was announced last April.

    Apart from the C4 Therapeutics and Proxygen collaborations, Merck vowed to shell out up to €893.5 million ($971.22 million) to Amphista Therapeutics to develop targeted protein degraders, back in 2022. Further, to accelerate the discovery of molecular glues and PROTACs, called on American biotech CelerisTx to employ its artificial intelligence (AI) platform to discover small molecule binders, in the same year.

    Roche is another multinational pharmaceutical that is glued to the protein degraders space. Its $50 million deal with American company Monte Rosa Therapeutics will allow it to use the latter’s QuEEN platform to target proteins that are difficult-to-drug, and treat cancer and neurological conditions. The QuEEN platform combines AI, proteomics and a variety of chemical libraries to discover and develop protein degraders.

    American biotech Genentech, which belongs to Roche, also signed a deal with Belgian life science company Orionis Biosciences to build a precision medicines portfolio led by molecular glues for undisclosed targets. The $47 million partnership, which could see Orionis eventually pulling in up to $2 billion in milestones, will utilize Orionis’ Allo-Glue technology. The Allo-Glue platform takes a ligase-centric approach in order to understand the ability of glue candidates to enhance protein-protein interactions. With the help of its platform, it can degrade, inhibit or change the function of target proteins, and treat diseases.

    Moreover, it kicked off a multi-project collaboration with British biotech PhoreMost in 2022. PhoreMost deployed its SITESEEKER platform to pin down targets for the pharma giant’s discovery program. PhoreMost’s platform is based on protein interference technology, as it probes the proteome – a set of proteins that are expressed in the body – of a cell for targets. 

    PhoreMost also joined forces with another U.K.-based biopharma, Sentinel Oncology, in conducting preclinical studies to test its PLK1 inhibitor against solid tumors.

    “We have an advanced collection of new E3 ligase ligands discovered using our SITESEEKER platform that we are progressing to our own degrader drugs, so we are deeply invested in protein degradation and stabilization modalities, including molecular glues. Discovery of new molecular glue degraders requires a highly systematic biology-led technology, and PhoreMost is uniquely positioned to pursue this major challenge,” said Cross. “We have recently adapted our platform to address this need and are very excited about our progress in neosubstrate discovery for MG development. We look forward to contributing to the advancement of this field.”

    And that’s not all. Bristol Myers Squibb has also followed suit and joined hands with New York-based AI-enabled drug discovery company VantAI to identify molecular glues, and potentially match them against validated drug targets. The AI-powered company is eligible to secure up to $674 million in milestone payments.

    Current research and clinical trials of molecular glues

    Meanwhile, a few studies testing molecular glues are underway as well. Chinese biotech Degron Therapeutics is currently studying cancer, inflammatory and metabolic disease targets with the help of its GlueXplorer platform. Its library of potential molecular glues are screened in three ways – through phenotypic screening to identify small molecules, proteomic analyses, and degradation screening of AI-predicted targets.

    Monte Rosa is also immersed in the field of molecular glue degraders. Apart from its collaboration with Roche, it is building an oncology pipeline of its own. Most advanced in its lineup is its clinical candidate MRT-2359, which is an oral molecular glue. MRT-2359 prompts the interaction between E3 ubiquitin ligase component cereblon (CRBN) and the translation termination factor GSPT1, to break down GSPT1, which aids tumor growth in cancers driven by the oncogene MYC. The candidate is undergoing a phase 1/2 trial to treat non-small cell lung cancer, small cell lung cancer, among other MYC-linked cancers.

    Also part of the molecular glues league is Magnet Biomedicine. Having emerged from stealth with $50 million last September, it aims to expand the scope of molecular glue drugs with the help of its TrueGlue discovery platform to address immune disorders, cardiovascular diseases, and cancer.

    Market size predicted to grow as more players enter the field

    As more biopharmas look to uncover the potential of molecular glues in treating a range of conditions, the market value is poised to cross $96 million by 2030, nearly double the size back in 2022.

    Cross pointed out that although the realization that some drugs act through a molecular glue mechanism is fairly recent, he expects more small molecule and biologic drugs that have been approved in the past to behave like molecular glues, shedding further light on the field.

    “Increased understanding of molecular glues has also coincided with a rise in the success of degrader-based drugs. Molecular glues are the smallest and simplest form of degraders, and may therefore be easier to progress preclinically, given their more traditional chemical properties in comparison to most bivalent degraders, which are often large and complex molecules,” said Cross. “This promise and new understanding has really amplified the excitement around molecular glue-based therapeutics.” 

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