RBPJ

Eli Lilly currently holds the throne as the world's most valuable pharmaceutical company by market capitalization. On July 15, 2024, Eli Lilly's stock price reached a historical high of $966.1 per share, with a company valuation of $910 billion, getting closer to becoming the first trillion-dollar valued pharmaceutical company. Eli Lilly's financial report for 2023 shows that its revenue mainly comes from dulaglutide ($7.133 billion), tirzepatide ($5.163 billion), abemaciclib ($3.863 billion), and ixekizumab ($2.76 billion), among others. With the continued volume growth of tirzepatide and the market launch of the new Alzheimer's drug Donanemab, the future remains promising. Eli Lilly's success is closely related to its inherent pragmatism. Although many of its products are not the first to be approved and launched, Eli Lilly's drugs are always present in popular targets and competitive fields, such as CDK4/6, IL-17, IL-23, and GLP-1. Eli Lilly's acquisitions are also discerning; for example, in September 2018, it acquired the GLP1 small molecule agonist Orforglipron from the Japanese company Chugai, which was still in the preclinical stage at the time. As Pfizer announced the discontinuation of the development of lotiglipron due to liver toxicity issues, Eli Lilly's Orforglipron has taken the lead globally, advancing to Phase 3 first. Compared to Eli Lilly's various successful acquisition cases, Gilead's acquisitions outside the viral field have almost entirely failed. For R&D personnel, this may serve as a guide to avoiding pitfalls. In the synapse database's transaction section, by selecting Eli Lilly as the transferee, one can see 129 transaction records. Among them, the transaction with PRISM BioLab on November 28, 2023, caught the author's attention. This licensing and cooperation agreement, which may total up to $660 million, aims to jointly develop oral small molecule drugs. PRISM BioLab utilizes its proprietary PepMetics technology to discover orally available small molecule inhibitors targeting protein-protein interaction (PPI) pathways, to treat patients with cancer, autoimmune, fibrotic, and other diseases. PepMetics are a unique class of small molecules that mimic the three-dimensional structures of α-helices and β-turns, which are common peptide structures in cellular PPIs and receptor-ligand interactions. According to the agreement, the two companies will collaborate to discover small molecule inhibitors of PPI targets selected by Eli Lilly through PRISM's proprietary PepMetics technology. Eli Lilly has the option to add two more targets to the collaboration and is responsible for the clinical development and commercialization of the resulting products. Although PRISM has already established cooperation with large pharmaceutical companies such as Eisai, Boehringer Ingelheim, Merck KGaA, and Roche, no intelligence information related to MNC companies has been found in either the pipeline or patent applications. In the patent section of the Synapse database, searching for patents applied for by PRISM BioLab yields over 211 entries. By limiting the publication date to the most recent five-year period, one can get a general sense of the company's research and development activities. The first six patents published include WO2023200017, WO2023140369, WO2023090366, WO2022158610, WO2022075486, and WO2022014724; half of these patents are related to inhibitors of the Notch signaling pathway. The Notch signaling pathway is an evolutionarily conserved mechanism that plays an indispensable role in the development and tissue homeostasis of mammals. Notch receptors and ligands contain single-pass transmembrane domains and are expressed on the cell surface; therefore, Notch signaling is particularly important in mediating communication between adjacent cells that express the receptors and ligands. In rodents and humans, four known Notch receptors have been identified, termed Notch 1 to Notch 4. Notch receptors are heterodimeric proteins composed of extracellular and intracellular domains that are initially synthesized as a single polypeptide. The receptor-ligand interaction triggers a series of proteolytic cleavages of the Notch receptor polypeptide, involving the activity of γ-secretase. The activity of γ-secretase cleaves the Notch intracellular domain (NICD) on the inner side of the plasma membrane, which then translocates to the nucleus to form a transcription factor complex. The Notch intracellular domain (NICD) is the active form of the protein. Various functions of Notch signaling include proliferation, differentiation, apoptosis, angiogenesis, migration, and self-renewal. Additionally, NICD activates the transcription of target genes Hes1 and Hes5 by translocating to the nucleus and forming a stable complex with RBP-J and MAML, which act as DNA-binding proteins. Therefore, compounds that can inhibit various functions of the Notch signaling pathway have the potential to become drugs for a variety of diseases involving these functions. A series of therapeutic strategies targeting the abnormalities of the Notch signaling pathway are currently under investigation and development. For instance, inhibitors of the Notch signaling pathway, such as γ-secretase inhibitors, are being studied and clinically trialed as potential treatment methods for acute lymphoblastic leukemia (ALL) and T-cell lymphoma (T-ALL). Based on the current state of Notch pathway inhibitors in clinical stages, the field is not yet crowded and is at a stage of interest to MNC companies. Eli Lilly and BMS show a high level of interest in this area. Eli Lilly has two molecules in clinical development: the Phase I LY3039478 and the discontinued LY900009. Eli Lilly's recent acquisition may also be related to collaboration on these pathway inhibitors. After all, PRISM BioLab's recent patents include three that belong to Notch inhibitors, with numerous examples in the patents and key molecules featuring more than three chiral centers. The most recently published patent, WO2023200017, has evolved from a bicyclic to a tricyclic heptamer, indicating that the synthesized molecules are becoming increasingly complex, which also demonstrates PRISM BioLab's significant focus on the Notch pathway. At present, drugs targeting the Notch signaling pathway are still under research. The Notch signaling pathway plays a crucial role in a variety of physiological processes, and intervention must be approached with caution to avoid severe toxic side effects. The regulatory mechanism of the Notch signaling pathway is complex, and how to precisely control it to achieve therapeutic effects remains an important direction for future research. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

Scientists mapped the gene regulatory networks responsible for progressive differentiation states of tumor-infiltrating T cells, using a technology known as single-cell CRISPR screening to knock out or genetically perturb multiple genes potentially involved. T cells are the key immune system component involved in killing cancer. Tumors produce signals that turn off these T cells, partially by forcing them to progressively differentiate (mature) into a hypofunctional state known as exhaustion. Scientists from St. Jude Children's Research Hospital comprehensively examined the transcription factors involved in T-cell differentiation states in cancer. They then used this information to enhance anticancer activity in preclinical models by promoting or blocking T-cell differentiation. The findings, which have implications for cancer immunotherapy, were published today in Nature. T cells are used in adoptive cell therapy (ACT) to target and kill cancer cells. Among ACTs, chimeric antigen receptor (CAR) T cells have shown clinical efficacy in blood cancers but have not been as effective in solid tumors. This variance in efficacy is partly because tumors promote T-cell exhaustion, in which the cells are less effective at actively killing cancer. The scientists showed they could precisely interrupt the flow of the differentiation process, thereby enhancing antitumor efficacy. "T cells are the cornerstone of tumor immunotherapy, and we found a new way to reprogram T cells to make them more effective," said Hongbo Chi, Ph.D., St. Jude Department of Immunology. "We can push them towards a specialized state so that they can be more functional tumor-killing cells." Modifying differentiation to flow toward cancer-killing T cells T-cell differentiation is conceptually similar to a river running down a mountain. The top of the mountain is the precursor cell, and the bottom an exhausted cell. The desired state is between these two extremes -- like having a lake in the middle of the mountain -- that is differentiated enough, but not too much, to have high proliferation and effective anticancer activity. The lake receives water from above but also has a stream constantly draining it further down the slope. Uninterrupted, all water in the lake will eventually drain through the river leading down below -- all the T cells will become exhausted. The scientists found a way to increase the water flow from above and dam the river draining the lake, resulting in more water accumulation in the lake or, more aptly, more T cells that effectively kill tumors. For example, when the researchers deleted the transcription factor ETS proto-oncogene 1 (ETS1), the amount of cancer-killing T cells was increased by enhancing differentiation to the intermediate state (increasing flow into the lake). On the other hand, knocking out the transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ) increased the accumulation of intermediate state T cells by blocking terminal differentiation (damming the river at the lake). Each approach showed markedly increased antitumor activity. Even more promising, when the researchers combined their modified T cells with a type of immunotherapy called immune checkpoint blockade, they further increased antitumor activity. "We've provided new potential strategies to enhance immunotherapy," said co-first author Peipei Zhou, Ph.D., St. Jude Department of Immunology. "We increased the amount of cancer-killing T cells by differentiating them from upstream precursors, and we could also block terminal differentiation to increase accumulation of the functional cells. Both approaches improved antitumor efficacy in our immune checkpoint blockade models." While the work was done in mouse models, the researchers used bioinformatics data from human clinical samples to verify that these same genes are important in these processes in humans. Mapping the differentiation journey of exhausted T cells T cells infiltrate tumors to go about their work of destroying them. The researchers mapped the transcription factors expressed in the T cells infiltrating tumors. Their work showed which individual transcription factors and their networks are responsible for each T cell differentiation state, providing targets for improving immunotherapy. "We created a map for the field of T-cell differentiation and exhaustion in tumors based on the loss-of-function genetic screening at high dimension," said co-first author Hao Shi, Ph.D., St. Jude Department of Immunology. "This map will provide a guide for future researchers to refer to and use to identify ways to improve T cell-based immunotherapies." Where past attempts to understand T-cell exhaustion focused on an individual molecule or transcription factor, this screen was more comprehensive. This allowed the researchers to document the entirety of the gene regulatory networks involved. "We've provided the most complete picture of the transcription factors in T cells inside a tumor ever created," Zhou said. "Such a causal transcriptional network provides new insights into lineage differentiation, a fundamental process in biology," added Shi. The group performed this feat using single-cell CRISPR-Cas9 screening, a gene editing technology that analyzes gene expression profiling of individual cells after selectively removing transcription factors in a comprehensive screen. Transcription factors are proteins that directly regulate gene expression. By examining an individual T cell's gene expression pattern, the researchers could compare them to see which knocked-out transcription factors most affected T-cell differentiation and anticancer activity. "The same approach may be more broadly applicable to increase our knowledge in many biological contexts beyond T cells and immunology," Chi said. "We showed this new technology, single-cell CRISPR screening in vivo, can drive novel biological discovery. I think we're at the advent of something truly exciting."

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. Another COVID-19 Vaccine Looks Promising According to the World Health Organization, there are 70 vaccines being developed worldwide for COVID-19, with three already in human clinical trials. The furthest along is one by CanSino Biologics and the Beijing Institute of Biotechnology, which is in Phase II. The others are by U.S. companies, Inovio Pharmaceuticals and Moderna. Another institution, the University of Pittsburgh, also announced that in laboratory tests their COVID-19 vaccine, delivered via a fingertip-sized patch, showed positive results in laboratory mice, producing antibodies specific to SARS-CoV-2 at enough amounts to neutralize the virus. The research was published in EBioMedicine , published by The Lancet. “We had previous experience on SARS-CoV in 2003 and MERS-COV in 2014,” said co-senior author Andrea Gambotta, associate professor of surgery at the Pitt School of Medicine. “These two viruses, which are closely related to SARS-CoV-2, teach us that a particular protein, called a spike protein, is important for inducing immunity against the virus. We know exactly where to fight this new virus. That’s why it’s important to fund vaccine research. You never know where the next pandemic will come from.” It uses a more traditional process than the mRNA one being used by Moderna. The virus is being called PittCOVacc, and uses laboratory-manufactured pieces of viral protein to build immunity. It’s a process similar to that used in seasonal flu shots. They also leveraged a new technique to deliver the drug, called a microneedle array, to increase the potency of the vaccine. The fingertip-sized patch has 400 tiny needles that deliver the spike protein pieces into the skin. It goes on like a Band-Aid. The needles are built from sugars and the antigens, and they just dissolve. “We developed this to build on the original scratch method used to deliver the smallpox vaccine to the skin, but as a high-tech version that is more efficient and reproducible patient to patient,” said Louis Falo, co-senior author and professor and chair of dermatology at Pitt’s School of Medicine and UPMC. “And it’s actually pretty painless—it feels kind of like Velcro.” They are currently submitting an Investigational New Drug (IND) with the U.S. Food and Drug Administration (FDA) and hope to begin Phase I human clinical trials in the next few months. Genetic Mechanisms of Inflammatory Bowel Disease Researchers at Children’s Hospital of Philadelphia identified a genetic variant that causes the development of inflammatory bowel disease (IBD). The pathway is linked to other immune disorders. More than 240 genetic regions are already associated with IBD, but each region has multiple markers and not all are causative. The researchers focused on the single nucleotide polymorphism (SNP) rs1887428, located on the promoter region of the JAK2 gene. The protein coded by the gene controls the production of blood cells. The team found that two transcription factors, RBPJ and CUX1, recognize the DNA sequence altered by the rs1887428 SNP, and while it only has mild influence on JAK2 expression, it was amplified by other proteins in the JAK2 pathway. Possible Mechanism of Link Between Obesity and Breast Cancer Breast cancer (and other cancers) and obesity are associated, but the reason for that link isn’t well understood. Researchers from the University of Louisville published research suggesting that the fatty acid binding protein family, especially FABP4, plays a critical role. Fat tissue produces FABP4 within fat cells, which processes and distributes water-insoluble long-chain fatty acids. Normally, some FABP4 enters the bloodstream, but the higher fat volume, the more FABP4 is secreted. They believe two mechanisms are in play. Within cells, FABP4 increases in certain tumor-associated macrophages, which accumulate in tumors and promote cancer growth. And second, when elevated levels of FABP4 circulate outside the fat cells, it promotes breast cancer by directly interacting with breast cancer cells. Using Cellular Machinery Without the Cells to Develop Drugs Northwestern University and ShanghaiTech University leveraged cell-free synthetic biology to produce a drug that kills SARS-CoV-2 in cell cultures. They indicate they could create the new drug by taking the molecular machinery out of cells and using that machinery to make a product in a safe, cheap and quick way. The molecule is called valinomycin. By using this method, they were able to increase production yields more than 5,000 times in only a few quick design cycles. Glucose Metabolism Linked to Alzheimer’s Disease Researchers with the National Institutes of Health’s National Institute on Aging conducted the largest study so far on proteins related to Alzheimer’s and identified proteins and biological processes that regulate glucose metabolism that are associated with Alzheimer’s. The study was published in the journal Nature Medicine . The study was part of the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD). The investigators assayed the levels and analyzed the expression patterns of more than 3,000 proteins in brain and cerebrospinal fluid samples collected at centers across the U.S. “This is an example of how the collaborative, open science platform of AMP-AD is creating a pipeline of discovery for new approaches to diagnosis, treatment and prevention of Alzheimer’s disease,” said Richard J. Hodes, NIA director. “This study exemplifies how research can be accelerated when multiple research groups share their biological samples and data resources.” The study involved analyzing protein expression patterns in more than 2,000 human brain and almost 400 cerebrospinal fluid samples taken from both healthy individuals and Alzheimer’s patients. They analyzed how the protein modules relate to Alzheimer’s and other neurodegenerative diseases. They observed changes in proteins related to glucose metabolism and an anti-inflammatory response in glial cells in brain tissues from both Alzheimer’s patients and people with documented brain pathology who were cognitively normal. This also would seem to support increasing evidence that brain inflammation is involved in the disease as well. In Alzheimer’s patients, they found that how cells extract energy from glucose is increased in both the brains and spinal fluid of Alzheimer’s patients. The proteins observed were also elevated in preclinical Alzheimer’s patients, which is to say, people with brain pathology of the disease who had not shown cognitive decline.