Gate Bioscience investment analysis

November 6, 2023

This is not investment advice. We used AI and automated software tools for most of this research. A human formatted the charts based on data / analysis from the software, prompted the AI to do some editing, and did some light manual editing. We did some fact checking but cannot guarantee the accuracy of everything in the article. We do not have a position in or a relationship with the company.

Overview

Gate Bioscience is a preclinical-stage biotech company specialized in developing "Molecular Gates", a new class of small molecule therapeutics designed to selectively block disease-causing extracellular proteins from being secreted by cells. Founded in 2021 and emerging with $60 million Series A funding from Versant Ventures, a16z Bio + Health, ARCH Venture Partners, and GV, the company's approach targets the secretory translocon—a cellular channel crucial for protein secretion.

With more than 1,000 extracellular proteins implicated in various diseases, including cancer, neurodegeneration, fibrosis and other disorders, the commercial potential of Gate's platform is vast.

As small molecules, molecular gates can potentially be administered orally and cross the blood-brain barrier. This distinguishes Gate Bioscience’s potential treatments from biologics and other larger molecule therapeutics, which typically face challenges in oral bioavailability and central nervous system penetration.

The company's next steps likely include preclinical validation of its therapeutic candidates, optimizing their drug-like properties, and conducting the necessary studies to progress to clinical trials. Given the early stage of the company, the focus will be on establishing proof-of-concept and safety profiles for their lead compounds.

Highlights and risks

Valuation

Given the early stage of the company and limited information about its programs, we did not conduct a valuation analysis.

Scientific approach

While specifics about Gate's programs are not available, we can speculate on how their approach works:

• Selective Translocon Modulation: The Molecular Gates are designed to interact with the secretory translocon—a complex that regulates the passage of proteins from the endoplasmic reticulum to the extracellular space. By specifically binding to the translocon, these molecules can theoretically discriminate between proteins based on their tertiary or quaternary structure, or through recognition of specific sequence motifs that are unique to disease-causing proteins.
• Molecular Targeting: The specificity for disease-causing proteins could be achieved through a lock-and-key mechanism where the Molecular Gate molecule has a complementary structure to a particular motif on the target protein. This would prevent the translocation of that protein without affecting others. The Molecular Gates might also exploit differences in the folding or post-translational modifications of disease-causing proteins versus normal proteins to achieve specificity.
• Protein Redirection for Degradation: Once the export of the targeted protein is blocked, the cell likely recognizes the accumulation of this unprocessed protein as abnormal. This could trigger quality control mechanisms such as the unfolded protein response, ultimately leading to the targeted degradation of the accumulated protein via pathways like the proteasome or autophagy.
• Discovery Platform Integration: The proprietary Molecular Gate Discovery Platform™ might employ advanced computational models and structural biology data to predict and validate the interaction between Molecular Gates and their protein targets. This could include high-throughput screening to empirically test small molecule candidates for their ability to block specific proteins at the translocon.
• Leveraging Existing Cellular Machinery: By using small molecules that are potentially orally bioavailable and can reach various tissues, including the brain, Gate Bioscience is likely leveraging the body’s own cellular machinery to aid in the selective degradation of targeted proteins. This approach may also allow for the ability to cross the blood-brain barrier, which is a significant challenge in drug design for neurodegenerative diseases.

The approach resembles that of targeted protein degradation strategies like PROTACs (proteolysis-targeting chimeras), but with a distinct focus on intercepting and degrading proteins during their synthesis and secretion pathway. The innovation here lies in the interception at an earlier, pre-secretory stage, which could have significant advantages in terms of preventing extracellular accumulation of pathogenic proteins, a key factor in many diseases.

The secretory translocon

The secretory translocon, primarily composed of the Sec61 complex in eukaryotic cells, is a fundamental component of the endoplasmic reticulum (ER) membrane that facilitates the translocation of newly synthesized polypeptides into the ER lumen or their insertion into the ER membrane. The ER is the entry point for proteins destined for secretion or residence in the endomembrane system and plasma membrane.

The Sec61 complex is the core of the translocon. It is formed by multiple subunits:

• Sec61α: This is the central subunit that forms the channel through which polypeptides pass. It has multiple transmembrane segments that create a pore within the ER membrane, with a lateral gate that can open to allow the integration of membrane proteins or remain closed for the translocation of soluble proteins.
• Sec61β: This subunit stabilizes the complex and plays a role in the opening and closing of the channel.
• Sec61γ: This also helps to stabilize the structure and may play a role in signal sequence recognition.

The Sec61 complex associates with additional components depending on the context, such as:

• Signal recognition particle (SRP): This ribonucleoprotein binds to signal sequences of nascent polypeptides on ribosomes and targets them to the ER.
• SRP receptor: This receptor, located in the ER membrane, recognizes the SRP-nascent chain complex and facilitates its delivery to the Sec61 translocon.
• Ribosome: The translocon is often closely associated with ribosomes, forming a ribosome-translocon complex that allows direct transfer of nascent proteins into the ER lumen.
• Translocon-associated protein (TRAP) complex: This complex assists in the translocation process, particularly for glycosylated proteins.

The translocon works as a highly selective gate, ensuring that only proteins with the appropriate signals are translocated or integrated. It can open and close in response to these signals, preventing ions and other small molecules from leaking across the ER membrane. The intricate workings of the translocon involve complex mechanisms that are not fully understood, such as how it distinguishes between proteins to be integrated into the membrane and those to be secreted into the ER lumen. The translocon has multiple functions:

• Protein translocation: As nascent polypeptides emerge from the ribosome, the translocon facilitates their entry into the ER. Signal sequences or transmembrane domains on the nascent protein interact with the translocon to initiate translocation.
• Protein integration into the membrane: Hydrophobic segments of membrane proteins interact with the lateral gate of Sec61α, integrating the protein into the lipid bilayer.
• Quality control: The ER lumen is the site of early protein folding and quality control. Proteins that fail to fold properly can be retro-translocated back through the translocon for degradation, a process called ER-associated degradation (ERAD).

The specificity and efficiency of the secretory translocon make it a compelling target for therapeutic intervention, as drugs that modulate its function could potentially influence the fate of numerous proteins, including those implicated in various diseases.

Gate's expertise in the secretory translocon

The involvement of scientific founders and advisors such as Pat Sharp, Rebecca Voorhees, Ramanujan Hegde, and Ville Paavilainen, who have demonstrated expertise in the mechanics of protein secretion and the function of the secretory translocon, particularly Sec61, provides deeper insight into the potential mechanisms that could be at play in Gate Bioscience's Molecular Gates technology.

Sec61 is a key component of the translocon complex at the endoplasmic reticulum (ER) membrane, acting as a channel through which nascent proteins are translocated into the ER lumen or integrated into the ER membrane. Here's how their expertise might inform and enhance the Molecular Gates technology:

• Selective Inhibition Knowledge: Pat Sharp’s work in demonstrating that small molecules can selectively inhibit protein secretion via Sec61 suggests that the Molecular Gates could be based on similar principles. This means that their small molecules might specifically block the Sec61 channel in a way that is selective for certain proteins, perhaps by recognizing unique features of disease-causing proteins as they engage with the translocon.
• Structural Biology Insights: The involvement of researchers like Rebecca Voorhees and Ramanujan Hegde, who have extensively studied the structure and function of the translocon, suggests that the design of Molecular Gates could be grounded in detailed structural insights. This could include understanding how proteins fold and interact with Sec61 as they translocate, allowing for the design of molecules that can distinguish between normal and disease-associated proteins based on their interaction with the translocon.
• Understanding of Protein Translocation Mechanics: Ville Paavilainen's work on the mechanisms of protein translocation provides an additional layer of understanding as to how proteins are moved into and across the ER membrane. This expertise could contribute to identifying unique stages in the translocation process that are most vulnerable to intervention and could be exploited to achieve the selectivity of Molecular Gates.
• Advanced Techniques: The scientific advisors’ experience with cutting-edge research techniques in molecular biology and biophysics, such as cryo-electron microscopy (cryo-EM), might enable the company to visualize the interaction between their small molecules and the Sec61 translocon at near-atomic resolution. Such visualization could be critical for refining the specificity and efficacy of their Molecular Gates.
• Translational Research: The knowledge of how to manipulate the Sec61 complex and the broader secretory pathway can be instrumental in transitioning from proof-of-concept studies in basic research to the development of drug candidates that can be tested in preclinical and clinical settings.

Technical and scientific risks

Developing therapies based on a mechanism like the Molecular Gates presents a range of challenges and limitations. Here are some key considerations:

• Selectivity and Specificity: Designing small molecules that can differentiate between thousands of proteins with high specificity is incredibly complex. In the case of Molecular Gates, they must recognize disease-causing proteins with high fidelity to avoid unintended inhibition of essential proteins. Ensuring specificity to the secretory pathway components they interact with is critical to avoid nonspecific interactions or blockage of the translocon.
• Complexity of the Secretory Pathway: The secretory pathway involves a series of complex, tightly regulated steps, and intervening in this process could lead to unexpected cellular responses or adaptive resistance.
• Protein Conformation: The target protein must be recognized by the molecular gate in its native conformation as it transits the secretory pathway. If the target protein adopts multiple conformations, designing a gate that consistently recognizes the disease-causing conformation can be difficult.
• Impact on the Secretory Pathway: Continuous or inappropriate blockade of the translocon could have downstream effects on the secretory pathway, leading to a buildup of proteins within the cell and potential cellular stress or apoptosis.
• Biogenesis and Trafficking: Molecular gates that interfere with protein secretion might also affect the biogenesis and trafficking of other proteins, leading to broader effects than intended.
• Reversibility and Regulation: Unlike PROTACs, which induce protein degradation, molecular gates must ideally allow for reversible modulation of protein secretion. Designing a system that can be regulated on-demand adds an additional layer of complexity. The concentration at which the gate is functional versus the concentration at which it disengages from the translocon would need to be clearly understood and precisely controlled.
• Complex Pharmacodynamics (PD): Molecular gates interfere with protein secretion by the secretory pathway, which is a highly dynamic and regulated process. This means the PD of molecular gates, which describes their biological and physiological effects and the mechanism of action, could be more complex. The precise control required to block the translocation of specific proteins without disrupting the entire secretory pathway would require a detailed understanding of the timing and regulation of protein secretion.
• Dosing Strategies: Determining the appropriate dosage would be complicated by the need to account for the variable rates of protein synthesis and secretion among different cell types. Additionally, the dose may need to be finely tuned to avoid complete shutdown of the protein’s secretion, unless that is the therapeutic goal.
• On-Target, Off-Tissue Effects: Even with a high degree of specificity for a target protein, the molecular gate might affect the target protein's secretion in tissues where its inhibition is not desired, leading to unintended pharmacological effects.
• Interpatient Variability: Different patients may have variations in the proteins that interact with the molecular gate or in the secretory pathway itself. This variability can lead to different responses to the same dosage, complicating the development of a one-size-fits-all dosing regimen.
• Pharmacokinetics (PK): The absorption, distribution, metabolism, and excretion (ADME) properties of molecular gates could be highly variable. Since they act intracellularly, their ability to penetrate cells and maintain stability within the cell is critical.
• Cellular Adaptation and Compensatory Mechanisms: Cells may adapt to the inhibition of protein secretion by activating alternative pathways or upregulating the production of the targeted protein.
• Drug-like Properties: Ensuring that these small molecules have appropriate pharmacokinetics and pharmacodynamics to reach their target site in vivo can be challenging, especially for brain targets due to the blood-brain barrier.
• Scalability and Manufacturing: The synthesis of complex molecules like PROTACs or Molecular Gates can be challenging and expensive, potentially limiting their scalability and increasing costs.

To manage these challenges, sophisticated pharmacological models would likely be necessary to predict how molecular gates behave in different tissues and under various physiological conditions. Extensive preclinical and clinical testing would be required to establish safe and effective dosing regimens. This may include the development of biomarkers to monitor the effects of the molecular gate and guide dose adjustments for individual patients.

Therapeutic applications

The strategy to selectively eliminate disease-causing extracellular proteins by targeting them inside the cell before they can be secreted and cause harm has the potential to impact a wide range of diseases. Moreover, because these are small molecules, they may have advantages in terms of tissue distribution, oral bioavailability, and the ability to cross the blood-brain barrier, which is particularly important for treating central nervous system diseases.

According to the company, there are over 1,000 extracellular proteins that are implicated in diseases, and theoretically all of these proteins can be targeted with Molecular Gates. The following diseases and conditions could be potential targets for their molecular gate therapies:

• Inflammatory Conditions: Many inflammatory diseases are driven by the overproduction or misregulation of cytokines and chemokines, which are secreted proteins that mediate and regulate immunity and inflammation. Conditions like rheumatoid arthritis, psoriasis, and inflammatory bowel disease could be potential targets.
• Neurodegenerative Diseases: These conditions often involve extracellular protein aggregates that are toxic to neurons. For example, Alzheimer's disease is characterized by the accumulation of beta-amyloid plaques outside neurons, while Parkinson's disease involves the aggregation of alpha-synuclein.
• Cancers: Some cancers are driven by growth factors and other signaling proteins that are secreted into the tumor microenvironment, promoting cell proliferation and survival. For example, certain breast cancers are driven by the overexpression of the HER2 protein, a receptor tyrosine kinase.
• Fibrotic Diseases: Fibrosis involves the excessive deposition of extracellular matrix proteins such as collagen, and can affect various organs such as the liver (in liver cirrhosis), lungs (in idiopathic pulmonary fibrosis), and kidneys (in chronic kidney disease).
• Cardiovascular Diseases: Abnormal levels of extracellular proteins such as lipoproteins and clotting factors can drive diseases like atherosclerosis and thrombosis, respectively.
• Rare Genetic Disorders: Diseases like cystic fibrosis or lysosomal storage disorders, which involve the misfolding and accumulation of specific proteins, could potentially be addressed by this technology.
• Autoimmune Disorders: Conditions such as systemic lupus erythematosus (SLE) involve autoantibodies and immune complexes that are present extracellularly and contribute to disease pathology.
• Infectious Diseases: In the context of infections, particularly chronic viral infections, secreted viral proteins can be targets for these molecular gate therapies to prevent the spread and assembly of new viral particles.

However, it's important to note that the specific targeting of disease-associated proteins without affecting the normal function of other proteins that go through the secretory pathway will be crucial for the safety and effectiveness of such therapies. The development of these drugs will likely require a deep understanding of the structure and function of both the translocon and the target proteins, as well as robust screening and testing to ensure specificity and efficacy.

More specifically, here are some diseases that could be good candidates for molecular glues:

Disease	Therapeutic Rationale for Molecular Gates	Existing Antibody/Other Therapies	Advantages of Molecular Gates Over Existing Therapies	Unmet Need	Challenges Using Molecular Gates	Potential Protein Targets
Rheumatoid Arthritis	Molecular gates could block pro-inflammatory cytokines directly at the source within cells.	TNF inhibitors (e.g., Humira, Enbrel)	Oral administration, potential for fewer side effects, and deeper tissue penetration.	Non-injectable treatments with fewer side effects.	Specificity in blocking only disease-related cytokines without disrupting normal immune function.	TNF-α, IL-6, IL-1β
Alzheimer's Disease	Prevent the secretion and subsequent aggregation of beta-amyloid plaques.	Monoclonal antibodies (e.g., Aduhelm)	Small molecules may cross the blood-brain barrier more effectively and modulate protein secretion.	Treatments that can halt or reverse disease progression.	Targeting the correct stage of amyloid protein for effective intervention; crossing the blood-brain barrier; molecular gates would not help clear existing plaques	Beta-amyloid precursor protein (APP)
HER2-positive Breast Cancer	Inhibit the secretion of the HER2 receptor tyrosine kinase.	Trastuzumab (Herceptin) and similar agents	Oral bioavailability, ease of administration, and potentially reduced immunogenicity.	Oral chemotherapy alternatives.	Achieving selective inhibition of HER2 without affecting other necessary receptor pathways; ensuring that the normal function of related receptors and cellular processes is not adversely affected.	Human Epidermal growth factor Receptor 2 (HER2)
Idiopathic Pulmonary Fibrosis	Reduce fibrotic extracellular matrix protein deposition.	Antifibrotic agents (e.g., Ofev, Esbriet)	Directly targeting the secretory pathway could prevent the secretion of fibrotic proteins.	More effective anti-fibrotic therapies with better outcomes.	Identifying and targeting the specific proteins responsible for fibrosis without impacting normal tissue repair; targeting a single protein may not suffice due to the multifactorial nature of the fibrotic process	Collagen, Fibronectin, TGF-β
Atherosclerosis	Control the levels of lipoproteins and clotting factors, or targeting inflammation in atherosclerosis.	Statins, PCSK9 inhibitors	Potential for more specific targeting of proteins involved in plaque formation.	Non-statin therapies for patients with hyperlipidemia intolerant to statins.	Balancing the reduction of harmful proteins while maintaining levels required for normal physiological processes.	Apolipoprotein B, PCSK9, Clotting Factors (e.g., Factor VIII)
Cystic Fibrosis	May help correct protein folding and trafficking of the CFTR protein.	CFTR modulators (e.g., Trikafta)	Small molecules that can potentially address proteins that do not respond to current CFTR modulators.	Treatments for CF patients who do not respond to current therapies.	Ensuring the correct folding and function of the CFTR protein while avoiding off-target effects; current CFTR modulators are very effective for certain mutations so new therapies would likely address non-responders.	Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
Systemic Lupus Erythematosus	Reduce the secretion of autoantibodies and immune complexes.	Biologics (e.g., Benlysta) and immunosuppressants	Oral administration and targeted suppression	Many patients have refractory disease despite current treatments, and long-term use of steroids and immunosuppressants leads to serious side effects.	Identifying specific extracellular targets without affecting the normal immune response could be challenging; target specificity is exceptionally challenging due to the diversity of autoantibodies involved in SLE.	Autoantibodies, BLyS (B lymphocyte stimulator)
Chronic Viral Infections	Preventing the secretion and assembly of viral components, potentially reducing viral load and disease progression.	Antiviral drugs, which may include direct-acting antivirals and host-targeted agents.	Could offer a new mechanism of action to overcome resistance to current antivirals, with potentially broad applicability across different viruses.	Resistance to current therapies, chronic infections require long-term management, and not all patients respond to existing therapies.	Targeting viral proteins without affecting host protein secretion, risk of resistance development, and viral diversity; not all viral proteins are secreted via the classical secretory pathway, so molecular gate technology may have limitations depending on the virus and its biology	Secreted viral proteins specific to each virus (e.g., hepatitis C virus (HCV) core protein, HIV gp120).

Potential first indication: rheumatoid arthritis

Of the above indications, rheumatoid Arthritis (RA) may be a compelling initial target for Gate Bioscience for several reasons:

• Well-Understood Pathophysiology and Biomarkers: RA is characterized by well-defined biomarkers, including specific cytokines such as TNF-α, IL-6, and IL-1β, which can be readily measured. The involvement of these cytokines in the disease is well established, which can help in designing targeted interventions.
• High Prevalence and Market Size: RA affects a large population worldwide, which represents a significant market opportunity for new therapeutic interventions. The market for RA treatments is also well established, which can help in forecasting the economic viability of a new product. Humira, one of the best-selling drugs of all time with over $20 billion in peak annual sales, targets rheumatoid arthritis.
• Unmet Medical Need: Despite the availability of biologics and disease-modifying antirheumatic drugs (DMARDs), there remains a subset of patients who do not respond adequately to existing therapies or experience severe side effects. This indicates a clear unmet need for new therapeutic options.
• Feasibility of Proof of Concept: Demonstrating proof of concept with a small molecule that can modulate cytokine levels could be achieved with a relatively small, targeted clinical trial, which is a key consideration for a startup with limited resources.
• Regulatory Pathway: RA has a clear regulatory pathway with established endpoints for clinical trials, which can expedite the development process.
• Competitive Landscape: While the RA treatment landscape is competitive, there is still room for treatments that offer advantages in terms of administration (oral vs. injectable), cost, and side effect profiles. Small molecules with a novel mechanism of action could be particularly attractive.
• Potential for Expansion: Success in RA could pave the way for expansion into other inflammatory and autoimmune diseases, allowing the company to leverage its technology platform across multiple indications.

Therefore, targeting RA as an initial focus could provide a strategic balance between scientific viability, clinical need, market potential, and regulatory clarity—all of which are crucial for a startup looking to establish itself in the biotechnology space.