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– Company creating de novo designed macrocycles with enhanced efficacy that precisely target disease biology – Vilya’s privileged macrocycles have the potential to be applied across broad therapeutic areas, addressing large unmet medical needs April 25, 2024 -- VILYA, Inc. (Vilya), a biotechnology company creating a new class of medicines that precisely targets disease biology, today announced the publication of a new study in Science that validates the company’s foundational drug discovery approach. The company’s platform, which is based on an exclusive license to the technology utilized in the study, leverages advanced computational approaches to design macrocycles with atomic-level accuracy that enable optimized drug-like properties. “Macrocycles are promising drug-like compounds, but incorporating diverse chemistries has historically been very difficult. We have now shown that we can accurately identify, design and synthesize small macrocycles using a new approach that leverages conformational analysis and chemical diversity to predict and construct macrocycles made out of a wide range of backbone building blocks with high structural fidelity to their design models,” said David Baker, Ph.D., Co-founder of Vilya, Director of the IPD, Professor of Biochemistry at the University of Washington, and publication co-author. “These findings indicate a promising direction for the future of drug design in which exploring diverse macrocycle structures could lead to the discovery of new therapeutic macrocyclic compounds with enhanced efficacy and specificity.” In the published paper, titled “Expansive discovery of chemically diverse structured macrocyclic oligoamides,” scientists at the Institute for Protein Design (IPD) at the University of Washington School of Medicine detailed a new proprietary computational method to design and predict the structure of small macrocycle compounds. This method significantly broadens the range of macrocycle chemical structures available for drug discovery beyond those found in nature. The study authors successfully synthesized and tested several of these computationally designed macrocycles, confirming that their actual structures closely match the predicted models. The study illustrated the therapeutic potential of these newly discovered macrocycles, which selectively inhibited a protein target of current interest they were designed to bind to. One of the three proteins designed against is the enzyme histone deacetylase (HDAC) 6, which regulates various cellular processes and has emerged as a therapeutic target involved in several types of cancer and neurodegenerative disorders. Results demonstrated that these designed macrocycles selectively and potently inhibited this target. Researchers also successfully applied this design approach to two other protein targets – mPro, the main protease of SARS-CoV-2 that plays a crucial role in the life cycle of the virus, and myeloid cell leukemia sequence 1 (MCL1), a protein that binds to BCL-2 antagonist/killer (BAK) and prevents it from signaling cell death. “This new study validates Vilya’s platform and is representative of the ongoing work we are doing in the field of medicinal chemistry to create small macrocycles, which are notable for their potent biological activities,” said Patrick J. Salveson, Ph.D., Co-founder and Chief Technology Officer of Vilya and lead author of the publication. “Our platform, which leverages our proprietary computational design, rapidly generates both chemically and structurally diverse drug-like macrocyclic compounds. In the short time since Vilya was founded in 2022, we have built a team and infrastructure to continue expanding our platform with increasing efficiency and to develop our emerging pipeline of promising macrocycles that could translate into revolutionary medicines.” Overall, the authors identified 14.9 million macrocycles built from a wide array of chemically diverse building blocks bonded together to form complex structures, showcasing a wide spectrum of drug-like macrocycles that could be used for novel bioactivities and structure-based drug design. They then synthesized a focused subset of 18 macrocycles and found the majority aligned closely to their predicted models, thereby validating the computational design approach. Nearly half of the macrocycles evaluated exhibited membrane permeability, or the ability to diffuse across tissue barriers and cell membranes. A majority also showed stability against serum proteases, underscoring their potential for effective pharmacokinetic profiles in vivo. Notably, the study authors designed macrocycles against HDAC6, of which the vast majority demonstrated potent inhibition, with select compounds achieving 100-fold to 1,000-fold selectivity over other HDACs. The macrocycles developed against the two other protein targets – mPro and MCL1 – highlight the generality of the developed methods. “Vilya was launched to leverage the foundational research in computational protein design pioneered by the team at the Institute for Protein Design and apply it to the creation of new macrocycle structures that could become transformative medicines for a variety of diseases,” said Cyrus Harmon, Ph.D., Chief Executive Officer of Vilya. “The publication in Science of the core capabilities of this technology, which we have licensed and integrated into our own proprietary platform, provides further validation of our approach. We are excited to continue building on this foundation that we have created over the past two years and advance several novel macrocycles toward clinical development.” Vilya’s proprietary platform, powered by advanced machine learning, taps into uncharted chemical space to design de novo molecular structures that are larger than most small molecules but much smaller than antibodies. These molecules are designed to have critical drug-like properties, including the ability to move through biological membranes and disrupt protein-protein interactions while being highly selective for their protein target. These novel artificial molecules with customized biologic-like properties can be leveraged for previously difficult-to-drug therapeutic targets in a broad set of indications. Vilya's computational design platform leverages advanced machine learning and other computational approaches to explore an exponentially larger chemical space than traditional discovery methods and to design in desired drug-like pharmacokinetic properties. The company’s ability to precisely design membrane-permeable molecules with high structural accuracy could lead to a new class of medicines that combine the advantages of traditional small molecule drugs and larger protein-based therapeutics. Vilya’s ability to create and screen a new class of target-directed, structured molecules in silico could transform drug discovery and development, potentially rendering high-throughput screening obsolete. Vilya is a computational biotechnology company creating a novel class of medicines to precisely target disease biology. The company’s proprietary platform, powered by advanced machine learning, taps into uncharted chemical space to design de novo molecular structures with enhanced drug-like properties that range in size between small molecules and antibodies. Vilya is leveraging its platform to focus on previously difficult-to-drug therapeutic targets. Vilya was co-founded by a team of scientists from the Institute of Protein Design (IPD), led by David Baker, Ph.D., and ARCH Venture Partners. The company has operations in Seattle and South San Francisco. To learn more, visit https://www.vilyatx.com. The content above comes from the network. if any infringement, please contact us to modify.

Researchers have traced the origin and evolutionary trajectory of plant immune receptors. Their discovery will make it easier to identify immune receptor genes from genomic information and could help in the development of pathogen-resistant crops. Plants are continuously evolving new immune receptors to ever-changing pathogens. Researchers at the RIKEN Center for Sustainable Resource Science (CSRS) have traced the origin and evolutionary trajectory of plant immune receptors. Their discovery will make it easier to identify immune receptor genes from genomic information and could help in the development of pathogen-resistant crops. This study was published in the scientific journal Nature Communications on February 1. As in animals, plants have immune responses that help them defend against pathogens such as viruses, bacteria, fungi, and oomycetes. Before invaders can be stopped, they must first be detected, and this is accomplished by pattern recognition receptors located on the surface of plant cells. The ability of these receptors to detect molecular patterns associated with pathogens depends on two types of proteins, called RLPs and RLKs, both of which can contain leucine-rich repeats -- sections in which the amino acid leucine appears multiple times. To trace the evolution of plant immunity, the international research team led by Ken Shirasu and Yasuhiro Kadota at RIKEN CSRS examined the numbers and patterns of receptors. They analyzed over 170,000 genes encoding RLKs and about 40,000 genes encoding RLPs, which they obtained from publicly available data taken from 350 plant species. They discovered that RLKs and RLPs with leucine-rich repeats were the most abundant receptor types among all the plant species, making up nearly half of RLKs and 70% of RLPs. RLPs, and some RLKs, are known to contain a special island region that is crucial for recognizing parts of pathogens. Investigation by the RIKEN CSRS team revealed that among RLPs that contain the leucine-rich repeats, this special region was almost always located in the same place; between the 4th and 5th leucine-rich repeat. These RLPs were found to be associated with immune responses. They also discovered that the island region was located at the same position in some RLKs, nearly all of which belong to a functional group that regulates growth and development. Comparative analysis showed that the sequence of the four repeats below the island region was very similar between the two types of protein detectors, suggesting that they have a common evolutionary ancestry. In particular, these four sets of leucine repeats contained sections needed for bonding to the same co-receptor, called BAK1. This means that immunity-related RLPs and growth-related RLKs inherited the ability to bind BAK1 from a common ancestor. "Intriguingly, we found that exchanging the four regions of leucine-rich repeats among these receptors did not disrupt their functionality," says Bruno Pok Man Ngou, who conducted the study. Creating a hybrid receptor by combining a growth-related RLK with an immunity-related RLP resulted in a hybrid receptor that recognized pathogens and induced both immune and growth-related responses. This means that scientists should be able to engineer receptors with new functions by swapping those modules. This study addressed the origins of plant immunity at a molecular level, showing that simultaneously analyzing information from multiple plant genomes can allow straightforward and precise prediction of genes involved in plant immunity and growth. "We are currently isolating immune receptors from various plants using this information, aiming for practical applications such as developing disease-resistant crops in the future," says Shirasu.

PT-112's mechanism of action inhibits ribosomal biogenesis, promoting immunogenic cancer cell death through cancer cell organelle stresses Data presented at the Society for Immunotherapy of Cancer's 38th Annual Meeting NEW YORK, Nov. 4, 2023 /PRNewswire/ -- Promontory Therapeutics Inc., a Phase 2 stage biotech company advancing immunogenic small molecule approaches in oncology, today presented data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells. Data suggest that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism. The presentation was made at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting, taking place November 1-5, 2023 in San Diego. The work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York, in order to elucidate the sequence of events – beginning with inhibition of ribosomal biogenesis and culminating in selective ICD – underlying PT-112's immune effects. Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to determine the impact of PT-112 on ER and mitochondrial stress, as well as immunogenic signaling. "Our continued studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling." Study findings include: PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD. PT-112 effects on mitochondria included increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1. PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR). There is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors, and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD. For more information about Promontory Therapeutics and PT-112, visit . About PT-112 PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112's mechanism of action governs intracellular events that cause the release of damage associated molecular patterns, known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response. PT-112's potential best-in-class ICD effects may create the conditions for effective and durable responses to treatment. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The company's Phase 2 study of PT-112 in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. An active Phase 2 trial is also on-going with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors, a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation. An additional Phase 2a study has been successfully completed for non-small cell lung cancer in combination with PD-L1 inhibition. About Promontory Therapeutics Promontory Therapeutics Inc. is a privately held, clinical stage drug development company focused on small molecule immunotherapy in cancer. The company's lead therapeutic candidate PT-112 has demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile across three Phase 1 studies. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castration-resistant prostate cancer in the United States and France, thymic epithelial tumors with the National Cancer Institute, and a completed Phase 2a trial in non-small cell lung cancer. As part of its recent research and development expansion into France, Promontory was selected as the first international company member of the Paris-Saclay Cancer Cluster, Europe's emerging biotech hub for oncology. To learn more about Promontory Therapeutics, visit the company's website here. CONTACTS: Promontory Therapeutics: Brooke Raphael, MS VP, Strategy & Operations Tel: +1 (646) 974-6453 Email: [email protected] Investors: Stan Musial Chief Financial Officer Tel: +1 (646) 222-6932 Email: [email protected] Media: Alexis Feinberg ICR Westwicke Tel: +1 (203) 939-2225 Email: [email protected] SOURCE Promontory Therapeutics Inc.