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December 2021 "30/11/2021 Confo will work together with Regeneron to apply its GPCR drug discovery platform VIB spin-off Confo Therapeutics today announced that it has entered into a collaborative agreement with Regeneron Pharmaceuticals, Inc. whereby Confo’s technology platform, which uses conformationally selective in disease-relevant conformations, will be applied with the goal of enabling the discovery of novel therapeutic

July 2022 Confo Therapeutics receives €1.7 million VLAIO grant for further research on GPCR modulators for rare diseases "29/06/2022 Confo Therapeutics, founded in 2015 as a spin-off from VIB and VUB, announced The grant should help expand Confo Therapeutic’s research on G protein-coupled receptor (GPCR) drug candidates

March 2022 Confo Therapeutics Doses First Subjects In Phase 1 Clinical Trial Of CFTX-1554 For The Treatment Of Neuropathic Pain "— Confo’s first drug candidate moves into clinical development — Ghent, Belgium – March 10, 2022 – Confo Therapeutics, a leader in the discovery of medicines targeting G-protein coupled

June 2022 "G protein-coupled receptors (GPCRs) represent a major therapeutic target class as they play In 2019, 5 out of 20 first-in-class approved therapeutic agents targeted GPCRs.

· Confo Therapeutics · Eli Lilly · GSK · Nabla Bio · Northeastern University · Nxera Pharma · OMass Therapeutics · Superluminal Medicines · Tectonic Therapeutics · and many more. Companies presenting include Skymab Biotherapeutics, Confo Therapeutics, GSK, Metaphore Biotechnologies , and Abilita Therapeutics. Tectonic Therapeutics on engineering a long-acting relaxin for pulmonary hypertension.

GPCRs in Cardiology, Endocrinology, and Taste Clinical, Pathophysiologic, Genetic, and Therapeutic Progress Secures $150 Million in Series B Financing to Advance Pipeline of Novel GPCR-targeted Medicines OMass Therapeutics Directors Crinetics Pharmaceuticals Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) Confo Therapeutics CEO, Cedric Ververken, will join WuXi AppTec's upcoming online series "BOLD: Innovation

GPCRs in Neuroscience Orphan receptor GPR88 as a potential therapeutic target for CNS disorders - an Industry News Coherus to Acquire Surface Oncology Confo Therapeutics and AbCellera partner on GPCR-targeting Patent in Japan Proteros Biostructures GmbH Revolutionizes Metabolic Disorder Treatments Structure Therapeutics (June 28 - 30, 2023) NEW FREE Seminar Antibodies targeting Membrane Proteins - From Antigen to New Therapeutics

This week's highlight: Congratulations to the GPCR Therapeutics team for their publication on improving Orion's COO, Shared Innovative Insights at LSBC Central European Life Science Investment Conference GPCR Therapeutics &D and Late-Stage Development Progress Parker Moss to Join Exscientia as EVP, Corporate Development Confo Therapeutics Nominated for 'Deal of the Year (>€500 Million)' Award at European Lifestars Awards GPCR

diffusion, offset kinetics, and rebinding ✅ Real-world examples of how residence time—not potency—predicts therapeutic The slow-offset compound stays on target longer, maintains therapeutic effect as concentrations drop, DrugResidenceTime #AllostericModulation #CytosolicKinetics #PK #PD #CellPermeabilityAssays #PAMPA #Caco2 #TherapeuticKinetics

Our partner, Domain Therapeutics, will attend the SACHS 23rd annual biotech event in Europe. Dr. Christopher Langmead and colleagues' work on the 5-HT2C receptor as a therapeutic target for substance GPCR Symposium on ''GPCRs as Therapeutic Modalities' Share your project with a 1-minute abstract video and G-CLIPS join forces to revolutionize transmembrane proteins characterization in drug discovery Confo Therapeutics Appoints Stephen Dowd As Chief Business Officer Septerna Announces Novel GPCR-targeted

Novartis bolsters innovative medicines strategy and renal pipeline with agreement to acquire Chinook Therapeutics Confo Therapeutics Enters Into Research Collaboration For GPCR-Targeting Antibody Discovery With AbCellera

from the atomic-level quaternary structure of short-lived GPCR oligomers in live cells Industry News Confo Therapeutics Announces EUR 60M Series B Financing to Advance a Pipeline of Novel GPCR-Modulating Therapies

GPCR Symposium on 'GPCRs as Therapeutic Modalities' Showcase your project with a 1-minute abstract video Bolsters Leadership Team as the Company Advances its Multi-Product Pipeline Toward Clinical Studies Confo Therapeutics Appoints Dieter Weinand, Former CEO Of Bayer Pharmaceuticals, As Independent Chairman Addex 21st Annual Global Healthcare Conference CEO Raymond Stevens to Speak at STAT Future Summit on Obesity Therapeutics Function and Biased Signaling" at the DOT NEW October 3, 2023 | FREE Seminar: Changing paradigm on Therapeutics

GPCR Symposium about 'GPCRs as Therapeutic Modalities' rocked it! recommended by NICE for acute migraines Addex mGlu2 NAM Cognition Program Receives €4 Million Grant Confo Therapeutics Appoints Stephen Dowd As Chief Business Officer Call for GPCR Papers opnMe GPCR Route 66 Lefkowitz's Career at Duke October 3, 2023, | FREE Seminar: Changing paradigm on Therapeutics targeting

November 7th : Drug Disposition in Physiological Tissues as a Therapeutic Variable. December 5th : Unique Exploitable GPCR-Ligand Behaviors for Therapeutic Benefit. Trial with SEP-786, a Novel Oral Small Molecule PTH1R Agonist for the Treatment of Hypoparathyroidism Confo Therapeutics Announces Publication in Nature Communications Demonstrating First-Ever Structure of a Complex Between an Antibody-based Agonist and a Class A GPCR Regulating Hunger and Satiety OMass Therapeutics

Industry News Design Pharmaceuticals has a new website Confo Therapeutics Announces Global Licensing Antiverse raises €2.8M for its computational antibody drug discovery platform Antiverse identifies therapeutic

cAMP-PKA-CREB signaling pathway based on network pharmacology and bioinformatics analysis Unveiling the therapeutic News Monash University pharmaceutical scientists honoured in NHMRC Research Excellence Awards Domain Therapeutics Clinical Study Evaluating Effects of NBI-1065890, a Second-Generation VMAT2 Inhibitor, in Healthy Adults Confo Therapeutics Secures VLAIO Grant Supporting Drug Discovery & Development In Endocrine And Metabolic Diseases How biotech companies are using AI to design drugs GPCR Therapeutics Announces Publication in

adipose tissue size more effectively than exendin, suggesting that biased agonism can lead to distinct therapeutic In conclusion, biased agonism at the GLP-1R represents a promising strategy for optimizing therapeutic continues to grow, it is likely to play an increasingly important role in the design of next-generation therapeutics Christopoulos, Signalling bias in new drug discovery: detection, quantification and therapeutic impact Drucker, D.J., Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1.  

Therapeutic potential of opioid receptor heteromers in chronic pain and associated comorbidities. Industry News Confo Therapeutics Enters into Collaboration Agreement with Daiichi Sankyo to Discover SMILES-based de novo molecular generation with curriculum and deep reinforcement learning Structure Therapeutics

July 2022 "July 19, 2022 07:00 AM Eastern Daylight Time BOSTON--Tectonic Therapeutic, Inc. a pre-clinical

A New Wave of GPCR Drug Discovery GPCRs are considered highly druggable, with GPCR-targeting therapeutics Within the last two years, three investments stand out: · Tectonic Therapeutics: received $80 USD Series A round to develop small molecule drugs against difficult-to-drug GPCRs. · Domain Therapeutics Developing Small Protein Therapeutics with a Novel Discovery Platform One way to overcome the challenges About Orion Biotechnology Orion’s mission is to unlock the therapeutic potential of previously undruggable

February 2022 "Ermium Therapeutics Announces the Formation of a Scientific Advisory Board comprising

May 2022 "Seoul, South Korea, 28 April 2022 – GPCR therapeutics, Inc., a venture-backed clinical stage

its best-in-class and first-in-class immuno-oncology programs STRASBOURG, France & MONTREAL- Domain Therapeutics

Historically, ligands for GPCRs have been identified before their receptor counterparts. With the cloning revolution, several unidentified receptors have been found and were labelled as “orphan” for their endogenous ligands. Orphan GPCRs have been shown to play key roles in various physiological functions, such as sensory perception, reproduction, development, growth, metabolism, and are also linked to major diseases, such as neuroinflammatory, metabolic and autoimmune diseases. Therefore, matching a ligand to an orphan GPCRs, the process of de-orphanizing, is of great importance in order to better understanding human physiology as well as to dissect the molecular mechanism governing the involvement of these receptors in human pathology. GPR84 is an example of an orphan GPCR (Sharman et al., 2011), although it is widely accepted that medium‐chain fatty acids (MCFAs) can bind to and activate this receptor with modest potency. GPR84 is a Gi‐coupled class A GPCR mainly expressed in immune cells and microglia in the brain (Wojciechowicz & Ma'ayan, 2020). GPR84 has been shown to be an attractive target in pro‐inflammatory conditions (Gagnon et al., 2018; Suzuki et al., 2013; Vermeire et al., 2017; Wojciechowicz & Ma'ayan, 2020) and efforts have been made to discover GPR84 antagonists. In this study Marsango et al. address two key questions in GPR84 biology and pharmacology: 1. how GPR84 expression profile correlates with physiological and pathological conditions? and 2. which ligands can be used as tool compounds to study the function and biology of this receptor? Regarding the first question, GPR84 overexpression in immune cells in a range of pro‐inflammatory disorders renders it a promising target in inflammatory and fibrotic conditions, including neuroinflammation (Audoy‐Remus et al., 2015), with ongoing clinical trials in idiopathic pulmonary fibrosis (Labéguère et al., 2014). GPR84 has been additionally proposed to be a potential biomarker in different inflammatory diseases (Arijs et al., 2011; Planell et al., 2017). Some studies have also reported GPR84 involvement in pain, atherosclerosis, and even metabolic disorders (Nicol et al., 2015, Audoy‐Remus et al., 2015, Du Toit et al., 2018). Regarding the second question, there is still a lot to be done in respect to tool compounds to study the function of this receptor towards clinical validation, as well as radiopharmaceuticals, including potential PET ligands, and suitable antibodies. Recent work has shown distinct functional outcomes of agonist ligands (Pillaiyar et al., 2018) with biased properties which can help to better elucidate the molecular pharmacology of this receptor. In addition, several GPR84 ligands have been described as well as GPR84 knockout mice. Among these ligands are orthosteric agonists such as alkylpyrimidine‐4,6‐diol derivatives (Liu et al., 2016; Zhang et al., 2016) and embelin (2,5‐dihydroxy‐3‐undecyl‐1,4‐benzoquinone) which is a natural product derived from the plant Embelia ribes (Gaidarov et al., 2018) which agonizes GPR84 but, interestingly, blocks the chemokine receptor CXCR2 and the adenosine A3 receptor (Gaidarov et al., 2018). IM (3,3′‐methylenebis‐1H‐indole) has been identified as a positive allosteric modulator of GPR84, a metabolite produced in vivo from indole‐3‐carbinol, which is present at high levels in some vegetables including broccoli and kale (Wang, Schoene, Milner, & Kim, 2012, Köse et al., 2020). GPR84 antagonists include a series of dihydropyrimidinoisoquinolinones (Labéguère et al., 2014), which behave as non‐competitive antagonists of GPR84 (Labéguère et al., 2020). From these series of compounds, GLPG1205 progressed into clinical development for the potential treatment of ulcerative colitis although it did not demonstrate sufficient efficacy (Labéguère et al., 2020). Overall, GPR84 is a promising target to exploit and the investment in better tools to study its function in both disease and physiological settings will likely potentiate drug discovery campaigns against this orphan GPCR. Check the original article at here! #GPCR #DrGPCR#Ecosystem

Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics

A Specific Difficulty, Not a General Verdict A pharmacologist designing an orthosteric small-molecule agonist for a family B GPCR encounters a pattern that recurs often enough to deserve a structural explanation. The molecule binds. The affinity is reasonable. The activation is weaker than the receptor's natural peptide agonist suggests it should be. The pattern is not universal, and it does not mean the orthosteric site is undruggable. It does mean that stabilizing the receptor's active state through a small molecule, at this specific class of GPCRs, is harder than orthosteric small-molecule programs at smaller receptors have led the field to expect. The reason has a structural account. It is one model among several, but it explains the observation cleanly, and it has practical consequences for how programs at peptide receptors approach modality choice. What GPCR Biologic Drugs Reveal About the Active-State Problem Family B GPCRs are conformationally malleable. The receptor samples many states. To produce agonism, a ligand must do more than occupy the binding pocket. It must stabilize the active conformation specifically, long enough for downstream signaling to proceed. GPCR biologic drugs, peptides in particular, achieve this through a mechanism worth naming carefully. A peptide agonist makes contact with the receptor across numerous regions of the binding site. Each contact contributes modestly. Together, they form what receptor pharmacologists describe as affinity traps: distributed networks of interactions that hold the receptor in an active state by satisfying many constraints at once. The active state is, on this account, the conformation in which the largest number of those contacts are simultaneously engaged. The peptide does not pull the receptor into activation. It selects for it, through the geometry of where its contacts can reach. Why an Orthosteric Small Molecule Has a Harder Time A small molecule binding the same orthosteric site engages fewer of those contact points. Not because small-molecule chemistry is weaker, but because a small molecule, by definition, occupies less of the binding region than a peptide does. This model suggests the consequence. The small molecule can show affinity for the site. It can produce binding. What it has more trouble doing is stabilizing the specific active conformation that the full peptide contact network selects for. The orthosteric site is the same site. The conformational outcome accessible from it depends on how much of the binding architecture a ligand can engage at once. Dr. Kenakin frames this carefully in the lecture: an orthosteric small molecule binds in only a few of the regions a peptide engages, and on this model, it will not stabilize the active state the same way. The framing is "seems to be difficult." Not impossible. Not categorically excluded. Difficult, for a reason that is structural rather than chemical. Why Allosteric Modulation Is the Productive Route The same structural account points toward the alternative that has been productive at these targets. An allosteric modulator does not need to engage the orthosteric contact network at all. It binds at a separate site, often on the receptor's extracellular surface or within a transmembrane domain, and influences the receptor's conformational equilibrium from there. The active state can be stabilized through a different geometric route, one that does not require the small molecule to reach across the full peptide binding region. Family B GPCRs have a rich history of allosteric ligands that produce activation. The argument is not that orthosteric small molecules are wrong at these receptors. It is that allosteric chemistry has a structural advantage when the goal is stabilizing an active state at a receptor whose natural agonist is a peptide. What This Means for Program Decisions The affinity-trap account, treated as a model rather than a verdict, has practical implications. It suggests that the difficulty an orthosteric small-molecule agonist program encounters at a family B GPCR may be a feature of the geometry, not a flaw in the chemistry. A series that shows good binding and weak activation, repeatedly, may be encountering the limit of what a small molecule can do at a site optimized over evolutionary time for peptide engagement. It also suggests that allosteric modulation deserves earlier consideration than it sometimes receives at these targets, and that biologic modalities, including peptides themselves, occupy a structural space orthosteric small molecules are not well positioned to fill. These are framing decisions, not prescriptions. The orthosteric site at a family B GPCR is not closed to small molecules. It is, on the affinity-trap account, a more difficult place to produce agonism than the same kind of site at a receptor whose natural ligand is itself small. Why Terry's Corner The affinity-trap account is one framework. The lesson it comes from develops what follows: biased signaling at peptide receptors, antibody-driven control of receptor disposition, the ADME and safety profile GPCR biologic drugs inherit, and the trafficking decisions that determine receptor fate inside the cell. These are pharmacological frameworks, and small-molecule intuition does not transfer cleanly to all of them. Terry's Corner is the room where pharmacologists work through frameworks like these alongside Dr. Terry Kenakin, with structured lessons as the foundation and live AMAs and workshops where the thinking comes alive. This is where receptor pharmacologists who take interpretation seriously sharpen their thinking together. 🟢 40 years of expertise at your fingertips: Explore the complete library ➤ ✳️ Want to know what's inside? Read the latest articles ➤ Stay sharp between lectures. Subscribe to The Kenakin Brief today ➤ Check out the YouTube Channel. https://www.youtube.com/@TerryPharmacologyCorner➤

Applications of Fluorescent Probes in Confocal Imaging of GPCRs: From Live to Fixed Cells GPCRs are present How Fluorescent Probes Enable High-Resolution Confocal Imaging of GPCRs To study the dynamics of GPCRs A High Content Screening focused microscope that has a confocal-like mode as well. Exploring the Applications of Confocal Fluorescence Microscopy in GPCR Research In GPCR research one Figure 2.Left panel, confocal microscopy of living cells incubated for 1h at 37ºC with CELT-327.

April 2022 Ono Enters into Collaboration Agreement with Domain Therapeutics and Université de Montréal : Gyo Sagara; “Ono”) today announced that it has newly signed a collaboration agreement with Domain Therapeutics

August 2022 Structure Therapeutics Extends Financing, Advances Diabetes and Obesity Clinical Program and Changes Name from ShouTi "San Francisco and Shanghai – August 1, 2022 – Structure Therapeutics Inc (Structure Therapeutics), formerly known as ShouTi Inc., today announced it closed an oversubscribed In addition, Structure Therapeutics has completed dosing in a single ascending dose (SAD) Phase 1 study