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September 2022 "The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for cancer therapy." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Dynamics of tumor-associated macrophages in a quantitative systems pharmacology model of immunotherapy in triple-negative breast cancer "Quantitative systems pharmacology (QSP) modeling is an emerging mechanistic computational approach that couples drug pharmacokinetics/pharmacodynamics and the course of disease progression. It has begun to play important roles in drug development for complex diseases such as cancer, including triple-negative breast cancer (TNBC). The combination of the anti-PD-L1 antibody atezolizumab and nab-paclitaxel has shown clinical activity in advanced TNBC with PD-L1-positive tumor-infiltrating immune cells. As tumor-associated macrophages (TAMs) serve as major contributors to the immuno-suppressive tumor microenvironment, we incorporated the dynamics of TAMs into our previously published QSP model to investigate their impact on cancer treatment. We show that through proper calibration, the model captures the macrophage heterogeneity in the tumor microenvironment while maintaining its predictive power of the trial results at the population level. Despite its high mechanistic complexity, the modularized QSP platform can be readily reproduced, expanded for new species of interest, and applied in clinical trial simulation." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "G protein-coupled receptor (GPCR) kinases (GRKs) and arrestins mediate GPCR desensitization, internalization, and signaling. The spatial pattern of GPCR phosphorylation is predicted to trigger these discrete GRK and arrestin-mediated functions. Here, we provide evidence that distal carboxyl-terminal tail (C-tail), but not proximal, phosphorylation of the chemokine receptor CXCR4 specifies βarrestin1 (βarr1)-dependent signaling. We demonstrate by pharmacologic inhibition of GRK2/3-mediated phosphorylation of the chemokine receptor CXCR4 coupled with site-directed mutagenesis and bioluminescence resonance energy transfer approaches that distal, not proximal, C-tail phosphorylation sites are required for recruitment of the adaptor protein STAM1 (signal-transducing adaptor molecule) to βarr1 and focal adhesion kinase phosphorylation but not extracellular signal-regulated kinase 1/2 phosphorylation. In addition, we show that GPCRs that have similarly positioned C-tail phosphoresidues are also able to recruit STAM1 to βarr1. However, although necessary for some GPCRs, we found that distal C-tail sites might not be sufficient to specify recruitment of STAM1 to βarr1 for other GPCRs. In conclusion, this study provides evidence that distal C-tail phosphorylation sites specify GRK-βarrestin-mediated signaling by CXCR4 and other GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2021 "Cannabinoids are abundant signaling compounds; their influence predominantly arises via engagement with the principal two G-protein-coupled cannabinoid receptors, CB1 and CB2. One suggested theory is that cannabinoids regulate a variety of physiological processes within the cells of skeletal muscle. Earlier publications have indicated that expression of CB1 receptor mRNA and protein has been recognized within myotubes and tissues of skeletal muscle from both murines and humans, thus representing a potentially significant pathway which plays a role in the control of skeletal muscular activities. The part played by CB1 receptor activation or inhibition with respect to these functions and relevant to targets in the periphery, especially skeletal muscle, is not fully delineated. Thus, the aim of the current research was to explore the influence of CB1 receptor stimulation and inhibition on downstream signaling of the nuclear receptor, NR4A, which regulates the immediate impacts of arachidonyl-2′-chloroethylamide (ACEA) and/or rimonabant in the cells of skeletal muscle. Murine L6 skeletal muscle cells were used in order to clarify additional possible molecular signaling pathways which contribute to alterations in the CB1 receptor. Skeletal muscle cells have often been used; it is well-documented that they express cannabinoid receptors. Quantitative real-time probe-based polymerase chain reaction (qRT-PCR) assays are deployed in order to assess the gene expression characteristics of CB1 receptor signaling. In the current work, it is demonstrated that skeletal muscle cells exhibit functional expression of CB1 receptors. This can be deduced from the qRT-PCR assays; triggering CB1 receptors amplifies both NR4A1 and NR4A3 mRNA gene expression. The impact of ACEA is inhibited by the selective CB1 receptor antagonist, rimonabant. The present research demonstrated that 10 nM of ACEA notably amplified mRNA gene expression of NR4A1 and NR4A3; this effect was suppressed by the addition of 100 nM rimonabant. Furthermore, the CB1 receptor antagonist led to the downregulation of mRNA gene expression of NR4A1, NR4A2 and NR4A3. In conclusion, in skeletal muscle, CB1 receptors were recognized to be important moderators of NR4A1 and NR4A3 mRNA gene expression; these actions may have possible clinical benefits. Thus, in skeletal muscle cells, a possible physiological expression of CB1 receptors was identified. It is as yet unknown whether these CB1 receptors contribute to pathways underlying skeletal muscle biological function and disease processes. Further research is required to fully delineate their role(s)." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Biased GPCR signaling by the native parathyroid hormone-related protein 1 to 141 relative to its N-terminal fragment 1 to 36 "The parathyroid hormone (PTH)-related protein (PTHrP) is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and bone remodeling, and causes hypercalcemia in patients with malignancy. Although mature forms of PTHrP in the body consist of splice variants of 139, 141, and 173 amino acids, our current understanding on how endogenous PTHrP transduces signals through its cognate G-protein coupled receptor (GPCR), the PTH type 1 receptor (PTHR), is largely derived from studies done with its N-terminal fragment, PTHrP1-36. Here, we demonstrate using various fluorescence imaging approaches at the single cell level to measure kinetics of (i) receptor activation, (ii) receptor signaling via Gs and Gq, and (iii) receptor internalization and recycling that the native PTHrP1-141 displays biased agonist signaling properties that are not mimicked by PTHrP1-36. Although PTHrP1-36 induces transient cAMP production, acute intracellular Ca2+ (iCa2+) release and β-arrestin recruitment mediated by ligand-PTHR interactions at the plasma membrane, PTHrP1-141 triggers sustained cAMP signaling from the plasma membrane and fails to stimulate iCa2+ release and recruit β-arrestin. Furthermore, we show that the molecular basis for biased signaling differences between PTHrP1-36 and properties of native PTHrP1-141 are caused by the stabilization of a singular PTHR conformation and PTHrP1-141 sensitivity to heparin, a sulfated glycosaminoglycan. Taken together, our results contribute to a better understanding of the biased signaling process of a native protein hormone acting in conjunction with a GPCR." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy "Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease that is expected to become the second cause of cancer fatalities during the next decade. As therapeutic options are limited, novel targets and agents for therapeutic intervention are urgently needed. Previously, we identified potent positive crosstalk between insulin/IGF-1 receptors and G protein-coupled (GPCR) signaling systems leading to mitogenic signaling in PDAC cells. Here, we show that a combination of insulin and the GPCR agonist neurotensin induced rapid activation of Src family of tyrosine kinases (SFKs) within PANC-1 cells, as shown by FAK phosphorylation at Tyr576/577 and Tyr861, sensitive biomarkers of SFK activity within intact cells and Src419 autophosphorylation. Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, short interfering RNA (siRNA)-mediated knockdown of YES1 and transfection of epitogue-tagged YAP mutants in PANC-1 and MiaPaCa-2 cancer cells, models of the aggressive squamous subtype of PDAC. Surprisingly, our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES and Src induces ERK over-activation in PDAC cells. Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor trametinib. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells and suppessed the growth of MiaPaCa-2 cells xenografted into the flank of nude mice. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g. trametinib) inhibitors in prospective clinical trials for the treatment of PDAC." Read more at the source #DrGPCR #GPCR #IndustryNews

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The 3rd edition of the Dr. GPCR Summit is between October 10th to the 16th! 💡Trainees are invited to participate by presenting a trainee talk, a poster, or a pre-recorded talk Become a site member for FREE and submit your info! ➡️ https://www.ecosystem.drgpcr.com/dr-gpcr-summit-2022 #gpcr #drgpcr

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We're very excited to announce the next episode of the Dr. GPCR podcast! 🥁 Drum rolls, please! Our guest is the wonderful Dr. Rosie Dawaliby! Watch the full video with a Dr. GPCR Ecosystem paid membership ➡️ https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-84-with-rosie-dawaliby #gpcr #drgpcr

🌟 We're so excited about our upcoming Dr. GPCR Summit 2022. This is a great opportunity for us to come together and talk GPCRs. Do you want to be part of it? Our Summit is FREE for all Ecosystem site members, which is also free! Join us now ➡️ https://www.ecosystem.drgpcr.com/dr-gpcr-summit-2022 #gpcr #drgpcr

December 2021 "Geneva, Switzerland, December 17, 2021 – Addex Therapeutics Ltd (SIX: ADXN and Nasdaq: ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based drug discovery and development, today announced that it has entered into a definitive agreement with Armistice Capital LLC, a healthcare-focused institutional investor, pursuant to which the Company agreed to sell 3,752,202 shares in the form of 625,367 American Depositary Shares (“ADSs”) at a gross purchase price of $6.50 per ADS, which is equivalent to CHF 1.00 per share. Each ADS represents six shares. Additionally, Addex has agreed to issue to Armistice Capital unregistered warrants to purchase up to 9,230,772 shares in the form of 1,538,462 ADSs (the “Unregistered Warrants”), as well as unregistered pre-funded warrants to purchase up to 5,478,570 shares in the form of 913,095 ADSs (the “Unregistered Pre-Funded Warrants” and together with the Unregistered Warrants, the “Warrants”) in a concurrent private placement. The Unregistered Warrants have an exercise price of $6.50 per ADS, will become exercisable in 60 days after their date of issuance and will expire six years from their date of issuance. The Unregistered Pre-Funded Warrants have been funded to the amount of $6.49 with $0.01 payable on exercise." Read more at the source #DrGPCR #GPCR #IndustryNews

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February 2022 "Switzerland Today, InterAx Biotech is pleased to announce that Carola Weiss has joined the company as VP Business Development. Carola Weiss is a Senior Executive with more than 20 years of international experience in the biopharmaceutical industry. Carola Weiss’ professional career brings deep expertise in business development, marketing & sales, licensing, alliance management, and strategic partnering. Her expertise guided numerous global negotiations, conclusions of partnership agreements, and fostered growth for her employers." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 "Watch our CEO Tim Dyer on AlphaStreet. In his interview, Mr. Dyer provides an overview of our #allostericmodulator pipeline and the potential $4 billion market for our lead compound #dipraglurant in #PDLID (#Parkinsonsdisease levodopa-induced #dyskinesia)." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 Exscientia and Sanofi Establish Strategic Research Collaboration to Develop AI-driven Pipeline of Precision-Engineered Medicines "Collaborative efforts aim to accelerate drug discovery and improve clinical success Agreement to utilize Exscientia’s AI-based capabilities and personalised medicine platform from target identification through patient selection Research will be focused on up to 15 novel small molecule candidates across oncology and immunology Exscientia will receive an upfront cash payment of $100 million with the potential of $5.2 billion in total milestones plus tiered royalties PARIS & OXFORD, England & BOSTON--Sanofi and Exscientia announced today a groundbreaking research collaboration and license agreement to develop up to 15 novel small molecule candidates across oncology and immunology, leveraging Exscientia’s end-to-end AI-driven platform utilizing actual patient samples. The companies have been working together since 2016 and in 2019, Sanofi in-licensed Exscientia’s novel bispecific small molecule candidate capable of targeting two distinct targets in inflammation and immunology." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "3-part randomized, double-blind, placebo-controlled Phase 1 study will evaluate TRV045 safety, tolerability, and PK in healthy volunteers Enrollment expected to start in early Q1 2022 CHESTERBROOK, Pa., Dec. 13, 2021 - Trevena, Inc. (Nasdaq: TRVN), a biopharmaceutical company focused on the development and commercialization of novel medicines for patients with central nervous system (CNS) disorders, today announced it is advancing TRV045 into clinical development, following receipt of a notification from the U.S. Food and Drug Administration (FDA) that the study may proceed. TRV045 is the Company’s novel S1P1 receptor modulator being developed as a potential treatment for diabetic neuropathic pain (DNP). In addition, through a collaboration with the National Institutes of Health, the Company is also exploring TRV045 as a potential treatment for epilepsy." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 Neurocrine Biosciences Announces Positive Phase 3 Data for KINECT-HD Study Evaluating Valbenazine for Chorea Associated with Huntington Disease "Highly Statistically Significant Reduction in Chorea Movements (p < 0.0001) as Measured by the Unified Huntington's Disease Rating Scale (UHDRS®) Total Maximal Chorea (TMC) Score- Placebo-Adjusted Mean Reduction in TMC Score of 3.2 Units in Valbenazine-Treated Patients- Company Plans to Submit Supplemental New Drug Application to U.S. Food and Drug Administration in 2022 SAN DIEGO, Dec. 7, 2021 /PRNewswire/ -- Neurocrine Biosciences (Nasdaq: NBIX) today announced positive top-line data from its Phase 3 KINECT-HD study evaluating the efficacy, safety and tolerability of valbenazine, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor being investigated as a once-daily treatment in adults with chorea associated with Huntington disease (HD). The study met the primary endpoint of reduction in severity of chorea, the cardinal motor feature in Huntington disease, as measured by change in the Unified Huntington's Disease Rating Scale (UHDRS®) Total Maximal Chorea (TMC) score from baseline to the average score at weeks 10 and 12. " Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "Dame Carol Robinson DBE, FRS, FRSC, FMedSci, Oxford University’s first female Professor of Chemistry, former president of the Royal Society of Chemistry and Founder of (and ongoing consultant to) OMass Therapeutics, which is based at Oxford Science Park, has been awarded the 2022 Louis-Jeantet Prize for Medicine. This is a highly prestigious international award – exemplified by the fact that other winners this year are the co-founders of BioNTech for their invention of the (Pfizer) Covid vaccine." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "Tokyo, Japan and Cambridge, UK, 24 December 2021 – Sosei Group Corporation (“Sosei Heptares”; TSE: 4565) today announces that in connection with the Collaboration and License Agreement (“License Agreement”) with Neurocrine Biosciences, Inc. (“Neurocrine Biosciences”) announced 22 November 2021, the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (“HSR Act”) expired on 22 December 2021. As such, the License Agreement became effective on 22 December 2021. With completion of the applicable waiting period under the HSR Act, under the terms of the License Agreement Neurocrine Biosciences has agreed to pay Sosei Heptares an upfront payment of US$100 million, with the amount to be recognized as revenue in the fourth quarter of the financial year ending December 31, 2021." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "Meet Peter McNamara, Ph.D., Tectonic’s SVP, Head of Research. Peter joined Tectonic to help chart new territory in GPCR science. We’re glad to have Peter's dedication, experience, and passion in building innovative therapeutics." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 "OXFORD, England--Professor Charlotte Deane, Ph.D., of the University of Oxford, has joined Exscientia as Chief Scientist of Biologics AI. In this newly created role, she will focus on the application of artificial intelligence (AI), machine learning, and the design of protein structures in the discovery and development of novel drug candidates. Professor Deane joins Exscientia’s technology leadership team, reporting to Chief Technology Officer, Garry Pairaudeau. Professor Deane is one of the UK’s most accomplished bioinformaticians. She has held numerous senior roles at the University of Oxford, where she is currently Professor of Structural Bioinformatics and leads the University’s Protein Informatics group. She will maintain both of these roles, in addition to her role at Exscientia. Prior to this, Professor Deane was Deputy Executive Chair of the Engineering and Physical Sciences Research Council at UK Research and Innovation (UKRI). She has played an active role during the COVID-19 pandemic as the UKRI’s COVID Response Director, and was a member of SAGE, the UK Government’s Scientific Advisory Group for Emergencies. Professor Deane holds a B.A. in Chemistry from the University of Oxford and a Ph.D. in Biochemistry from the University of Cambridge." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 "G-protein-coupled receptors’ star has been on the rise in biotech in recent years as researchers have discovered the vast potential for GPCR-targeting drugs in treating a range of health conditions, from cancer and genetic disorders to inflammation and metabolic imbalances. Among those hitching their wagons to that star are Verily and Sosei Heptares, which have struck a research agreement to discover new GPCR targets that’ll fuel the development of potential drug candidates. The financial details of the strategic collaboration weren’t released, but Sosei Heptares’ past two team-ups in GPCR-based drug discovery have clocked in at $1 billion—with Genentech—and, just last November, $2.6 billion in a partnership with Neurocrine." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 "The Neurocrine Biosciences story puts into words what makes the work and people at Neurocrine Biosciences so special. It captures our values and vision for the future, our culture, and our unique approach to science. Simply put, it represents what we do and why we do it. Hear the story from our colleagues in this video." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 ChemoCentryx Announces EU Approval of TAVNEOS® (avacopan) for the Treatment of ANCA-Associated Vasculitis "SAN CARLOS, Calif., Jan. 19, 2022, today announced that TAVNEOS® (avacopan) has been approved within the European Union in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA), the two main forms of ANCA-associated vasculitis. This approval follows the U.S. Food and Drug Administration (FDA) approval of TAVNEOS in October 2021. TAVNEOS will receive marketing authorization in all member states of the European Union, as well as in Iceland, Liechtenstein and Norway." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 "After securing FDA approval for Wegovy last year, Novo Nordisk is strengthening its position in the obesity space through a collaboration with EraCal Therapeutics. Under the joint research plan, the Danish giant will work with EraCal to identify novel drug targets relevant for food intake regulation and additional metabolic phenotypes. Although specific details of the collaboration are yet to be released, EraCal has confirmed that the duo will utilise its phenotypic drug discovery platform to identify potential targets." Read more at the source #DrGPCR #GPCR #IndustryNews

February 2022 Septerna emerges with $100M to spark 'second golden age' of prolific drug target GPCR with pioneer as co-founder "Jan 27, 2022 07:00am Septerna wants to spark a second golden age in G-protein-coupled receptor drug discovery. Better known as GPCR, the fruitful research space has led to more than 700 approved drugs over previous decades—but the two-year-old biotech believes the area is still ripe for development, and it now has $100 million to help power its efforts. The company's co-founder, GPCR pioneer and Nobel laureate Robert Lefkowitz, M.D., has 50 years of experience with the target and analogizes the search for new drugs to oil drilling around the world." Read more at the source #DrGPCR #GPCR #IndustryNews

February 2022 "InterAx Biotech AG and Boehringer Ingelheim take first steps towards collaborating to unlock orphan targets leveraging InterAx AI driven discovery platform. Collaborative efforts aim to accelerate and improve the prediction of first-in-class small molecule agonists for a challenging orphan GPCR for a highly relevant therapeutic need. 💊 InterAx Biotech AG discovery platform was already successfully applied in projects with biopharmaceutical companies and also used in-house to discover first-in-class compounds for a novel oncology target that are now being tested in-vivo. #ai #biotech #systemsbiology #drugdiscovery #gpcr #deeptech #orphandrugs #pharma #partnerships #AI4drugdiscovery" Read more at the source #DrGPCR #GPCR #IndustryNews