7 Companies Using AI to Design Protein Degraders
Our cells function in the continuous mode of producing and degrading proteins, keeping the balance between these two processes to maintain a healthy cellular function. However, sometimes the produced proteins might be defective, accumulating and causing pathological effects. This is one of the examples when hijacking the naturally occurring process of protein degradation becomes highly useful for rescuing the cells.
When the time comes, in the majority of cases ubiquitin-proteasome system (UPS) takes over proteins. The sequence of enzymatic reactions leads to marking doomed proteins by the ubiquitin chain, which is done by E3 ubiquitin ligase. This causes the signaling cascade and, consequently, proteasomal recycling of proteins into the new building blocks.
Scientists figured out a way to force E3 ubiquitin ligase to get in proximity with any protein of interest so that the UPS can be involved in the targeted protein degradation -- by applying "molecular glues" or proteolysis-targeting chimeras, or PROTACs, the two most popular strategies to go about protein degradation.
Molecular glues and PROTACs -- what, why, and how?
Molecular glues are small molecules that stick two proteins together: typically a pathological protein and E3 ubiquitin ligase. With this reaction, molecular glues induce the poly-ubiquitinylation of “unwanted” proteins, which otherwise wouldn’t happen or would have a significantly slower rate. Nonetheless, a simple concept challenges the drug design process: the small molecule should bind one protein and modify its 3D structure so that it can bind the other protein of interest. A not-straightforward process makes the molecule’s structure prediction process more vague and complex.
Another approach in targeted protein degradation -- proteolysis-targeting chimeras, or PROTACs -- might resolve some of the molecular glue design challenges but simultaneously bring new ones. In brief, while molecular glue is a single molecule that embodies all the functions in one module, PROTACs are bifunctional molecules. This means they have separate domains binding E3 ligase and POI, joined by a linker in between, altogether resembling a dumbbell-shaped object. In recent years PROTACs discovery went through accelerated growth, with multiple companies signing new collaborations and adding protein degraders to their pipeline profiles.
RELATED: Protein Degraders Take Industry By Storm
Even though PROTACs are promising, they have several significant limitations. First of all, the POI should have a druggable pocket to bind the chimera’s domain, but only a subset of proteins is considered druggable. Additionally, a bigger size of PROTACs might lead to bioavailability challenges. Potentially, molecular glues might help to overcome these limitations.
The molecular glues industry is heating up
Recently molecular glues started attracting more attention from multiple investors and induced deals between big pharma companies and biotech start-ups. In October 2022, it was announced that Bristol Myers Squibb partnered up with San Francisco-based biotech SyntheX to develop targeted protein degraders therapeutics. The collaboration will be focused explicitly on discovering molecular glue degraders. Under the terms of the agreement, SyntheX will receive a combined upfront payment and up to $550 million in performance-based milestone payments.
SyntheX has developed proprietary platforms that leverage the power of synthetic biology to build next-generation drug discovery engines. This allows the company to discover functional molecular glues using a pre-specified E3 ligase and a POI.
Shortly after SyntheX’s deal, also in October 2022, Nested Therapeutics raised $90 million from a series A round to fund a molecular glue program.
As Nested's CSO and co-founder Klaus Hoeflich commented:
“Our platform uses insights from various fields, including genomics, structural biology, computational biophysics, and artificial intelligence. This opens doors to designing novel small molecules for previously known targets with well-understood biology and to target what has been previously undruggable".
Earlier this year, in May 2022, Bristol Myers Squibb and Merck KGaA also collaborated with UK-based Amphista Therapeutics, where the last one can potentially earn $2.3 billion in this deal. The company has focused on building its targeted protein degradation platform called Eclipsys, which aims to target and remove toxic and troublesome proteins instead of just inhibiting their potentially harmful functions.
In June 2022, Merck KGaA also made a $554 million deal with Austria-headquartered biotech Proxygen, which specializes in molecular glue therapies. Proxygen aims to develop a broad net of novel molecular glues.
AI-powered companies in the molecular glues field
Since molecular glues discovery and design have significant challenges, but also considerable potential, multiple companies are trying to address the task involving artificial intelligence-driven platforms.
Some might say it is impossible to create the molecular glue molecule from scratch since predicting an atomic configuration is particularly complicated. In contrast to designing PROTACs, where researchers can take two ligand-binding domains and connect them with the linker, molecular glues are just one small molecule making one protein bind to another. In this case, researchers should find the molecule which not only binds one protein but also induces such configurational changes that this protein will stick to another one. This is where artificial intelligence (AI) could come in extremely handy, helping create new paradigms for designing PROTACs and molecular glues.
Herewith, we are reviewing several companies applying cutting-edge artificial intelligence platforms to design proteid degrades and, speaking broadly, targeted protein modulators.
Triana Biomedicines
Founded in 2019, US biotech Triana Biomedicines uses a deep-learning algorithm to develop molecular glues. Their technology allows identifying molecules that promote the interaction between a target and another protein in a way that alters the fate or function of the target protein. Triana utilizes AI-powered in silico algorithm to predict protein surface features and select complementary E3 ligases to the defined targets. They also build E3 ligase-biased molecular glue libraries based on structural biology insights and screening data. The company has a multidirectional toolbox of biophysical methods and functional assays in physiologically relevant contexts to identify and optimize molecular glues.
Celeris Therapeutics
California and Austria-based Celeris Therapeutics was founded in January 2021, aiming to utilize AI technology to discover proximity-inducing compounds (PICs), focusing on PIC degraders for Parkinson's disease and various types of cancers. The company’s AI-driven platform Celeris One involves structure-based geometric deep learning to prioritize specific E3 ligases and select active compounds for synthesis. An in-house generated experimental data is then used for additional optimization cycles. Using an AI-powered platform, Celeris Therapeutics determines the strength of the interaction between molecules in an automated manner based on the 3D information of the surfaces of proteins and ligands and their physicochemical features. It helps to predict the modification of the target molecule surface after binding the new chemical entities, followed by running interaction predictions between the modified target and E3 ligase.
Monte Rosa Therapeutics
Monte Rosa Therapeutics is Switzerland-based biotech founded in 2018, specializing in cancer therapeutics that modulate protein degradation pathways. The company uses AI-powered deep neural net the identify therapeutically relevant protein targets that may be targeted with molecular glue degraders and designs the molecules that can be optimized towards high potency and selectivity. Their proprietary platform QuEEN (Quantitative and Engineered Elimination of Neosubstrates) aims to uncover the molecular interactions between degrons on the surface of therapeutically relevant proteins and E3 ligases. Degrons are elements on proteins that act as ubiquitin ligase recognition signals for protein degradation by the UPS.
With a degron encyclopedia, molecular glue degraders library, and glueomics toolbox Monte Rosa pushes their drug candidates to clinical trials. In September 2022, they announced FDA clearance for the company’s investigational new drug application for MRT-2359, a selective GSPT1-directed molecular glue. The company is on track with initiating a phase 1/2 clinical trial in patients with MYC-driven solid tumors, including lung cancer, and expects to dose the first patient in Q4 of 2022.
Plexium
California-based Plexium was founded in 2018, aiming to use targeted protein degradation to treat cancer and other diseases. The Plexium Platform combines the screening of purposefully designed “on-bead” DNA encoded libraries (DELs) in high-throughput miniaturized cell-based assays that directly measure the degradation of one or more proteins of interest in a disease-relevant cellular context. The platform allows the potential assessment of a full range of E3 ligases within a cell. Plexium also has a partnered program with Amgen in their pipeline, aimed at developing novel molecular glues and monovalent degraders. In April 2022, they signed a deal with Abbvie to develop and commercialize targeted protein degradation therapies for neurological conditions.
BioTheryX
BioTheryX is a clinical-stage biopharmaceutical company founded in 2007 and based in New York. By using their PRODEGY platform, they designed molecular glues, bifunctional degrades, and hybrid degraders, with the BTX-1188 molecular glue drug candidate currently going through phase 1 clinical trials. The molecule can be potentially used to treat hematological malignancies and solid tumors. BioTheryX’s platform integrates a range of structure-based computational tools and machine-learning algorithms with a portfolio of biological assays, screening methodologies, and high-throughput synthesis capabilities. They apply expertise in Cereblon modulation (a substrate receptor of the E3 ligase complex), having customized computational chemistry methods and a library of over 4,000 small molecules designed to bind Cereblon.
Degron Therapeutics
Shanghai-headquartered Degron Therapeutics was founded relatively recently, in April 2021, aiming to discover novel molecular glue degraders for cancer treatment and other therapeutic areas. The company spun out of the lab of cofounder Yong Cang, a professor at ShanghaiTech University, and is based at JLabs, an incubator of Johnson & Johnson. In June 2022, Degron raised $22 million in series A financing, which will be used to advance the company's GlueXplorer platform. GlueXplorer is a molecular glue-based targeted protein degradation platform aiming to accelerate the development of novel drugs for previously undruggable targets in oncology, inflammation, metabolic disease, rare diseases, and other therapeutic areas. Degron's platform uses a combination of phenotypic screening, proteomic screening, and AI to predict novel targets and accelerate compound discovery.
C4 Therapeutics
US-based C4 Therapeutics was founded in 2016 and went public in October 2020. The company has a portfolio with both molecular glue degraders and PROTACs, not giving preference to only one class of protein degraders. The company owns a proprietary C4T TORPEDO (Target ORiented ProtEin Degrader Optimizer) platform chemistry engine that enables the designing, optimization, analysis, and activity prediction of degrader molecules. Using their C4T platform for both bifunctional and monofunctional protein degraders allows for addressing multiple targets with various approaches; for example, they currently have a molecular glue drug candidate in phase 1 trials, indicated for multiple myeloma and lymphoma. Additionally, C4 Therapeutics has multiple collaborations with Roche, Biogen, and Calico.
Topic: AI in Bio
