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September 2022 "Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 GASP1 enhances malignant phenotypes of breast cancer cells and decreases their response to paclitaxel by forming a vicious cycle with IGF1/IGF1R signaling pathway "There is a potential correlation between G-protein-coupled receptor-associated sorting protein 1 (GASP1) and breast tumorigenesis. However, its biological function and underlying molecular mechanism in breast cancer have not been clearly delineated. Here, we demonstrated that GASP1 was highly expressed in breast cancers, and patients harboring altered GASP1 showed a worse prognosis than those with wild-type GASP1. Functional studies showed that GASP1 knockout significantly suppressed malignant properties of breast cancer cells, such as inhibition of cell proliferation, colony formation, migration, invasion and xenograft tumor growth in nude mice as well as induction of G1-phase cell cycle arrest, and vice versa. Mechanistically, GASP1 inhibited proteasomal degradation of insulin-like growth factor 1 receptor (IGF1R) by competitively binding to IGF1R with ubiquitin E3 ligase MDM2, thereby activating its downstream signaling pathways such as NF-κB, PI3K/AKT, and MAPK/ERK pathways given their critical roles in breast tumorigenesis and progression. IGF1, in turn, stimulated GASP1 expression by activating the PI3K/AKT pathway, forming a vicious cycle propelling the malignant progression of breast cancer. Besides, we found that GASP1 knockout obviously improved the response of breast cancer cells to paclitaxel. Collectively, this study demonstrates that GASP1 enhances malignant behaviors of breast cancer cells and decreases their cellular response to paclitaxel by interacting with and stabilizing IGF1R, and suggests that it may serve as a valuable prognostic factor and potential therapeutic target in breast cancer." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Experimental studies proposed a direct effect of follicle-stimulating hormone (FSH) on the skeletal metabolism, but results of human studies mainly conducted in females are controversial. The present study aims to investigate the possible role of FSH excess in male bone health, by comparing for the first time primary and central hypogonadism." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations "The δ-opioid receptor (DOR) is a critical pharmaceutical target for pain management. Although the high-resolution crystal structures of the DOR with both agonist and antagonist have recently been solved, the activation mechanism remains to be elusive. In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular dynamic (MD) simulations were conducted to probe the activation mechanism. While the receptor with the crystal ligand (i.e. antagonist naltrindole) maintained the inactive conformation in all three independent simulations, the receptor with ADL5859 was adopting toward the active conformation in three out of six independent simulations. Major conformational differences were located on transmembrane (TM) 5 and 6, as well as intracellular loop 3. Compared to naltrindole, ADL5859 exhibited high conformational flexibility and strong interaction with the transmission switch. The putative key residues (W274, D95, V267, L139, V263, M142, T260, R146, R258 and others) involving in the activation pathway were identified through the conventional molecular switch analysis and a pairwise distance analysis, which provides a short list for experimental mutagenesis study. These insights will facilitate further development of therapeutic agents targeting the DOR.Communicated by Ramaswamy H. Sarma." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Background Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. Methods We propose formulas for the Driver Strength Index (DSI) and the Normalized Driver Strength Index (NDSI), the latter independent of gene mutation frequency. We validate them using TCGA PanCanAtlas datasets, established driver prediction algorithms and custom computational pipelines integrating SNA, CNA and aneuploidy driver contributions at the patient-level resolution." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 β2-Adrenergic Receptor Expression and Intracellular Signaling in B Cells Are Highly Dynamic during Collagen-Induced Arthritis "The sympathetic nervous system (SNS) has either a pro-inflammatory or anti-inflammatory effect, depending on the stage of arthritis. In the past, treatment of arthritic B cells with a β2-adrenergic receptor (β2-ADR) agonist has been shown to attenuate arthritis. In this study, the expression and signaling of β2-ADR in B cells during collagen-induced arthritis (CIA) were investigated to provide an explanation of why only B cells from arthritic mice are able to improve CIA. Splenic B cells were isolated via magnetic-activated cell sorting (MACS). Adrenergic receptors on B cells and intracellular β2-ADR downstream molecules (G protein-coupled receptor kinase 2 (GRK-2), β-Arrestin 2, p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB)) were analyzed at different time points in naïve and arthritic B cells with and without stimulation of β2-ADR agonist terbutaline by flow cytometry. β2-ADR-expressing B cells increase during CIA without a change in receptor density. Moreover, we observed a profound downregulation of GRK-2 shortly after induction of arthritis and an increase in β-Arrestin 2 only at late stage of arthritis. The second messengers studied (p38, ERK1/2 and CREB) followed a biphasic course, characterized by a reduction at onset and an increase in established arthritis. Stimulation of CIA B cells with the β-ADR agonist terbutaline increased pp38 MAPK independent of the timepoint, while pERK1/2 and pCREB were enhanced only in the late phase of arthritis. The phosphorylation of p38 MAPK, ERK1/2 and CREB in the late phase of arthritis was associated with increased IL-10 produced by B10 cells. The change of β2-ADR expression and signaling during sustained inflammation might be an integral part of the switch from pro- to anti-inflammatory action of sympathetic mechanisms in late arthritis." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P1-5. S1P5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, our structure with S1P5-inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The function of the actin cytoskeleton in cellular motility and trafficking has been widely studied. However, reorganization of the actin cytoskeleton upon modulation of membrane cholesterol and its consequences on membrane dynamics are addressed only rarely. In a recent work, we reported that chronic cholesterol depletion using statins leads to significant polymerization of the actin cytoskeleton. In this work, we explore the effect of reorganization of the actin cytoskeleton on membrane dynamics under cholesterol-depleted condition. Specifically, we explore the role of actin cytoskeleton in regulating the dynamics of the serotonin1A receptor, a crucial neurotransmitter G protein-coupled receptor (GPCR) that plays a major role in the generation and modulation of cognitive and behavioral functions. For this, we analyzed the lateral dynamics of the serotonin1A receptor in cholesterol-depleted cells (using statins) by fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) measurements. Our results indicate that lateral diffusion parameters of serotonin1A receptors in normal cells are consistent with models describing the diffusion of molecules in a homogeneous membrane. Interestingly, these parameters are altered in cholesterol-depleted cells and the receptor exhibits dynamic confinement. Notably, our results show that statin-induced dynamic confinement could be reversed by destabilization of the actin cytoskeleton. On a broader perspective, these results assume significance in understanding the modulatory role of the membrane environment on the organization and dynamics of GPCRs in diseases caused by altered cholesterol biosynthesis." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Isoforms of GPR35 have distinct extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway bias "Within the intestine, the human G protein-coupled receptor (GPCR) GPR35 is involved in oncogenic signaling, bacterial infections, and inflammatory bowel disease. GPR35 is known to be expressed as two distinct isoforms that differ only in the length of their extracellular N-termini by 31 amino acids, but detailed insights into their functional differences are lacking. Through gene expression analysis in immune and gastrointestinal cells, we show that these isoforms emerge from distinct promoter usage and alternative splicing. Additionally, we employed optical assays in living cells to thoroughly profile both GPR35 isoforms for constitutive and ligand-induced activation and signaling of 10 different heterotrimeric G proteins, ligand-induced arrestin recruitment, and receptor internalization. Our results reveal that the extended N-terminus of the long isoform limits G protein activation yet elevates receptor-β-arrestin interaction. To better understand the structural basis for this bias, we examined structural models of GPR35 and conducted experiments with mutants of both isoforms. We found that a proposed disulfide bridge between the N-terminus and extracellular loop 3, present in both isoforms, is crucial for constitutive G13 activation, while an additional cysteine contributed by the extended N-terminus of the long GPR35 isoform limits the extent of agonist-induced receptor-β-arrestin2 interaction. The pharmacological profiles and mechanistic insights of our study provide clues for the future design of isoform-specific GPR35 ligands that selectively modulate GPR35-transducer interactions and allow for mechanism-based therapies against, for example, inflammatory bowel disease or bacterial infections of the gastrointestinal system." Read more at the source #DrGPCR #GPCR #IndustryNews

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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

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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