April 2022 Sosei Heptares Confirms Senior Leadership Changes to Drive the Company Through the Next Stage Matt Barnes appointed President of Heptares Therapeutics Ltd., and Head of UK R&D Tokyo, Japan and Cambridge

Among those hitching their wagons to that star are Verily and Sosei Heptares, which have struck a research The financial details of the strategic collaboration weren’t released, but Sosei Heptares’ past two team-ups

November 2021 "Cambridge’s Japanese-owned life sciences company Sosei Heptares has clinched a lucrative

December 2021 "Tokyo, Japan and Cambridge, UK, 24 December 2021 – Sosei Group Corporation (“Sosei Heptares the HSR Act, under the terms of the License Agreement Neurocrine Biosciences has agreed to pay Sosei Heptares

August 2022 "August 10, 2022 Cancer Research UK is working with global biopharma Sosei Heptares on a

"We recently hosted our annual Scientific Advisory Board (SAB) summit at our site within Granta Park. It was great to bring everyone together and also welcome new member John Parkinson." Read more at the source #DrGPCR #GPCR #IndustryNews

May 2022 Sosei Heptares and Kallyope Enter Collaboration to Identify and Validate Novel Gastrointestinal GPCR Targets for Drug Discovery "Collaboration is part of Sosei Heptares’ Target Identification and leverage multiple sophisticated technologies that drive creation of new drug discovery programs in key therapeutic pioneers in drug discovery involving the gut-brain axis, will gain unique and valuable access to the Sosei Heptares biology platform to identify potential GPCR targets and advance the development of new gastrointestinal therapeutics

July 2022 Cancer Research UK and Sosei Heptares sign agreement to advance cancer immunotherapy candidate largest private funder of cancer research, today announce the signing of an agreement to bring Sosei Heptares

December 2022 Sosei Heptares Enters Antibody Discovery Agreement with Twist Bioscience to Discover and Develop Novel Therapeutic Antibodies against GPCR Targets "Collaboration aims to combine Twist’s proprietary synthetic antibody libraries and sophisticated bioinformatics expertise with Sosei Heptares’ world-leading high-quality synthetic DNA using its silicon platform, announced a strategic collaboration to discover therapeutic antibodies against G protein-coupled receptors (GPCR) identified by Sosei Heptares."

February 2022 Read more at the source #DrGPCR #GPCR #IndustryNews

April 2022 "By Cliona MacSweeney | Apr 20, 2022 Cliona MacSweeney, a project director in our Translational Medicine department, recently presented this important pre-clinical work at SIRS2022 confirming the ability of the highly selective novel GPR52 agonist HTL00411718 to modulate centrally mediated locomotor activity in response to A2A receptor antagonists. This work highlights an important interplay between the adenosinergic and dopaminergic systems and suggests the potential for GPR52 agonists to control neuropsychiatric symptoms in conditions such as schizophrenia. " Read more at the source #DrGPCR #GPCR #IndustryNews

Sophie Bradley | Apr 12, 2022 Summary Sophie Bradley, Translational Sciences Associate Director at Sosei Heptares recently presented at the Keystone Symposia GPCR Conference, a summary of work performed both at Sosei Heptares the role of the muscarinic M1 receptor in cognitive and neurodegenerative disorders and the potential therapeutic

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

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.  

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

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

July 2022 "I’m happy to share that I’m starting a new position as Scientific co-founder LASEREDD Therapeutics

March 2022 "Explicyte grants Domain Therapeutics exclusivity on data related to GPCR implicated in immunoresistance Strasbourg and Bordeaux, France, March 10, 2022 – Domain Therapeutics, a biopharmaceutical company specializing their expertise to identify GPCR targets and associated biomarkers to discover and develop breakthrough therapeutic

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➤

former president of the Royal Society of Chemistry and Founder of (and ongoing consultant to) OMass Therapeutics

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

September 2022 "Background G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3’s functions and clinical utility in GAC progression and metastases are unknown. Methods We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "Despite the importance of members of the GPCR superfamily as targets of a broad range of effective medicines many GPCRs remain poorly characterised. GPR84 is an example. Expression of GPR84 is strongly up regulated in immune cells in a range of pro-inflammatory settings and clinical trials to treat idiopathic pulmonary fibrosis are currently ongoing using ligands with differing levels of selectivity and affinity as GPR84 antagonists. Although blockade of GPR84 may potentially prove effective also in diseases associated with inflammation of the lower gut there is emerging interest in defining if agonists of GPR84 might find utility in conditions in which regulation of metabolism or energy sensing is compromised. Here, we consider the physiological and pathological expression profile of GPR84 and, in the absence of direct structural information, recent developments and use of GPR84 pharmacological tool compounds to study its broader role and biology. " Read more at the source #DrGPCR #GPCR #IndustryNews