April 2022 Trevena Receives up to $40M in OLINVYK ex-US Royalty-Based Financing from R-Bridge Healthcare Fund, an affiliate of CBC Group " CHESTERBROOK, Pa., March 31, 2022 -- 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 that the Company entered into a royalty-based financing with an affiliate of R-Bridge Healthcare Fund (the R-Bridge Financing)." 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

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

April 2022 Sosei Heptares Confirms Senior Leadership Changes to Drive the Company Through the Next Stage of its Evolution "New team focused on expanding its GPCR-focused structure-based drug design platform and enhancing translational medicine capabilities • ‘Venture-like’ capital allocation approach to focus pipeline development through to Phase 1b/2a clinical proof of concept in patients, and optimize value generation • Mid-term global expansion plans include drug discovery technology investments, licensing late-stage products for Japan, and strategic acquisitions • Mr. Chris Cargill appointed as President and Chief Executive Officer • Dr. Matt Barnes appointed President of Heptares Therapeutics Ltd., and Head of UK R&D Tokyo, Japan and Cambridge, UK, 24 March 2022 – Sosei Group Corporation (“the Company”; TSE: 4565) today confirms that a series of Executive Management changes have been approved at the Company’s 32nd Shareholders’ Meeting today and are effective immediately (see biographies at the end)." Read more at the source #DrGPCR #GPCR #IndustryNews

April 2022 Design Pharmaceuticals Closes $5 Million Pre-series A Round to Accelerate Commercialization of Ultrahigh Throughput Drug Discovery Platform " April 12, 2022 07:00 AM Eastern Daylight Time CAMBRIDGE, Mass.-- Design Pharmaceuticals , a company redesigning small molecule drug discovery, today announced the closing of a pre-series A round of $5 million, including an investment of $3 million from Virtus Inspire Venture Partners. The proceeds will be used to further build the company’s discovery platform and operations. Design Pharmaceuticals ’ platform is based on ultrahigh-throughput technologies that biomine drug-like molecules from natural sources, such as microbiota. These molecules are then evaluated at unprecedented speed and scale on hundreds of GPCR targets simultaneously." Read more at the source #DrGPCR #GPCR #IndustryNews

April 2022 Addex Expands Pipeline With Selective M4 Positive Allosteric Modulator Program For The Treatment Of Schizophrenia & Other Psychotic Disorders " New Series of Potent and Selective Compounds Identified Using Proprietary Allosteric Modulator Screening Platform Ad Hoc Announcement Pursuant to Art. 53 LR Geneva, Switzerland, April 6, 2022 - Addex Therapeutics (SIX: ADXN and Nasdaq: ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based drug discovery and development, announced today that it has moved a selective and potent M4 muscarinic receptor positive allosteric modulator (PAM) program into lead optimization. M4 PAMs have the potential to treat schizophrenia and other types of debilitating neuropsychiatric disorders." Read more at the source #DrGPCR #GPCR #IndustryNews

April 2022 Addex Therapeutics Completes Patient Enrollment For Dipraglurant Blepharospasm Phase 2 Clinical Study " Geneva, Switzerland, April 13, 2022 - Addex Therapeutics Ltd (SIX: ADXN, Nasdaq: ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based drug discovery and development, announced today that patient enrollment has been completed in its Phase 2a clinical study evaluating dipraglurant as a potential treatment for blepharospasm, a type of dystonia characterized by involuntary contractions or spasms of the eyelid muscles. Dipraglurant selectively targets the metabotropic glutamate receptor subtype 5 (mGlu5) through allosteric modulation to downregulate the neurotransmission believed to cause blepharospasm." Read more at the source #DrGPCR #GPCR #IndustryNews

March 2022 Inversago Pharma Announces Dosing of First Participant with Metabolic Syndrome in Phase 1B Clinical Trial " MONTREAL (CANADA) – March 15, 2022 – Inversago Pharma Inc. (“Inversago”), a clinical stage biotech company with a unique portfolio of CB1 inverse agonists, announced today the dosing of the first participant with metabolic syndrome in a Phase 1b clinical trial. This 28-day trial will test the pharmacokinetics and safety profile of Inversago’s lead molecule, INV-202, on a targeted population with metabolic syndrome. Topline results from 40 subjects are expected in the second half of the calendar year." Read more at the source #DrGPCR #GPCR #IndustryNews

March 2022 "Congratulations to Richard J. Law , our newly named Chief Business Officer. Richard is the architect behind nearly all of Exscientia's partnerships and collaborations across pharma and #biotech⁠ and is an advocate for the role of #AI in drug discovery." Read more at the source #DrGPCR #GPCR #IndustryNews

March 2022 " Explicyte grants Domain Therapeutics exclusivity on data related to GPCR implicated in immunoresistance, to develop first-in class innovative cancer therapies. Strasbourg and Bordeaux, France, March 10, 2022 – Domain Therapeutics , a biopharmaceutical company specializing in the discovery and development of new drugs targeting G Protein-Coupled Receptors (GPCRs) in immuno-oncology (IO), and Explicyte , an expert in the field of IO and innovative target identification through multiparametric approaches, announce today the signing of a partnership agreement. The two companies will combine their expertise to identify GPCR targets and associated biomarkers to discover and develop breakthrough therapeutic programs for IO. Financial terms are not disclosed." Read more at the source #DrGPCR #GPCR #IndustryNews

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 receptors (GPCRs), today announced that the first subjects have been dosed in the company’s Phase 1, first-in-human trial of their clinical candidate CFTX-1554, a novel inhibitor of the angiotensin II type 2 receptor (AT2R). CFTX-1554 is being developed as a non-opioid approach to the treatment of neuropathic pain, a debilitating condition caused by damage to the nerves outside of the brain and spinal cord, for which current treatment methods are often insufficiently effective and can lead to serious side effects and addiction. The Phase 1 study will assess the safety, tolerability and pharmacokinetics of CFTX-1554 in healthy subjects (NCT05260658). " Read more at the source #DrGPCR #GPCR #IndustryNews

March 2022 Crinetics Pharmaceuticals Expands Executive Team With Appointment Of James Hassard As Chief Commercial Officer "SAN DIEGO – March 1, 2022 – Crinetics Pharmaceuticals , Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, today announced the appointment of James Hassard as chief commercial officer. Mr. Hassard is a commercial leader with more than three decades of experience leading sales and marketing operations for both global and domestic biotechnology companies." Read more at the source #DrGPCR #GPCR #IndustryNews

Are you ready? Tomorrow is the day for another Dr. GPCR Virtual Cafe. This time with none other than Dr. Bryan Roth There are 10 open tickets available. Get yours now! https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe/ #gpcr #drgpcr #virtualcafe

Mark your calendars! The Dr. GPCR Podcast is back this week with a brand new episode. Our guest is none other than Dr. Juan Jose Fung, Principal Scientist, at GPCR Therapeutics. Stay tuned as the episode will be released later this week. Subscribe today! https://buff.ly/32fzGbO #gpcr #drgpcr #podcast

Next on the Dr. GPCR Podcast, we have none other than Dr. Marta Filizola! Subscribe to the podcast today and get notified when new episodes are released! You can also leave us a review on Apple Podcast! https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ #gpcr #drgpcr #podcast

Mark your calendars and get your ticket today! The Dr. GPCR Virtual Cafe is back! Our first guest speaker is none other than Dr. Ben Myers! Learn about communication between GPCRs and PKA, Class F GPCR Smoothened & the Hedgehog signaling pathway! https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe

Next on the Dr. GPCR Podcast, we have Dr. Pina Cardarelli, CSO of GPCR Therapeutics. Subscribe to the podcast today and get notified when new episodes are released! ecosystem.drgpcr.com/dr-gpcr-podcast/ #gpcr#drgpcr #podcast

February 2022 "We are proud to announce the success of our IPO! Thank you to our shareholders, both historical and new, for their trust. The €25 million fundraising gives us the means to achieve our ambitions: to become a leading player in the field of brain diseases! #IPO #biotech #innovation #traitements #addiction #cannabis #Trisomie21 #Downsyndrome" Read more at the source #DrGPCR #GPCR #IndustryNews

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

February 2022 Trevena Announces Submission of New Drug Application in China for OLINVYK® by its Partner Jiangsu Nhwa Pharmaceutical "Submission supported by data from a Phase 3 bridging study of oliceridine injection compared to IV morphine, conducted in China by Nhwa Trevena is eligible to receive future success payments upon approval and commercialization milestones, as well as a 10% royalty on net sales in China CHESTERBROOK, Pa., Jan. 27, 2022 A biopharmaceutical company focused on the development and commercialization of novel medicines for patients with central nervous system (CNS) disorders, today announced that China’s National Medical Products Administration (NMPA) has accepted submission of a New Drug Application (NDA) for oliceridine injection. The NDA was submitted by Trevena’s partner, Jiangsu Nhwa Pharmaceutical, and follows completion by Nhwa of a Phase 3 bridging trial for OLINVYK (oliceridine) injection, a novel IV analgesic that has been approved in the United States by the Food and Drug Administration (FDA) for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate." Read more at the source #DrGPCR #GPCR #IndustryNews

Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimer Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology. Read full article

Episode 55 of the Dr. GPCR podcast is now available! Our guest is Mark Schmeizl! He is a pro at Matchmaking the top talent in the life sciences with the industry’s leading companies. Listen where you get your podcasts https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ #drgpcr #gpcr #podcast

January 2022 "We are an experienced, innovative, global team on a bold mission to improve health by creating and developing life-changing medicines for people around the world." 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

A role for BET proteins in regulating basal, dopamine-induced and cAMP/PKA-dependent transcription in rat striatal neurons The activity of striatal medium-spiny projection neurons is regulated by D1 and D2 dopamine receptors. The D1 receptor (D1R) is a Gαs/olf-coupled GPCR which activates a cAMP/PKA/DARPP-32 signalling cascade that increases excitability and facilitates plasticity, partly through the regulation of transcription. Upon activation via D1R, PKA can translocate to the nucleus to regulate transcription through the phosphorylation of various targets. One candidate effector of PKA-dependent transcriptional regulation is the BET protein Brd4. It is known that when Brd4 is activated by phosphorylation, it binds more readily to acetylated histones at promoters and enhancers; moreover, in non-neuronal cells, PKA signalling has been shown to increase recruitment of Brd4 to chromatin. However, it is unknown whether BET proteins, or Brd4 specifically, are involved in transcriptional activation by cAMP/PKA in neurons. Here, we demonstrate that in adult rats, inhibition of BET proteins with the bromodomain inhibitor JQ1 suppressed the expression of ~25% of D1R-upregulated genes, while also increasing the expression of a subset of immediate-early genes. We further found that cAMP/PKA signalling promotes Brd4 recruitment to dopamine-induced genes in striatal neurons, and that knockdown of Brd4 attenuates D1R-induced gene expression. Finally, we report that JQ1 treatment downregulated expression of many GPCRs and also impaired ERK1/2 signalling in striatal neurons. Our findings identify the BET protein family, and Brd4 in particular, as novel regulators of basal and D1R-dependent transcription in rat striatal neurons, and delineate complex bi-directional effects of bromodomain inhibitors on neuronal transcription. Read full article

Retinitis pigmentosa (RP) is a group of hereditary degenerative diseases affecting 1 of 4000 people worldwide and being the most prevalent cause of visual handicap among working populations in developed countries. These disorders are mainly related to the abnormalities in the rod G protein-coupled receptor (GPCR), rhodopsin reflected in the dysregulated membrane trafficking, stability and phototransduction processes that lead to progressive loss of retina function and eventually blindness. Currently, there is no cure for RP, and the therapeutic options are limited. Targeting rhodopsin with small molecule chaperones to improve the folding and stability of the mutant receptor is one of the most promising pharmacological approaches to alleviate the pathology of RP. This review provides an update on the current knowledge regarding small molecule compounds that have been evaluated as rhodopsin modulators to be considered as leads for the development of novel therapies for RP. Read full article

Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor CXCR4 WHIM syndrome is a rare immunodeficiency disorder that is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. While several gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor CXCR4 have been identified in WHIM syndrome patients, the functional effect of these mutations are not fully understood. Here, we report on a new WHIM syndrome mutation that results in a frame shift within the codon for Ser339 (S339fs5) and compare the properties of S339fs5 with wild type CXCR4 and a previously identified WHIM syndrome mutant, R334X. The S339fs5 and R334X mutants exhibited significantly increased signaling compared to wild type CXCR4 including agonist-promoted calcium flux and extracellular signal-regulated kinase activation. This increase is at least partially due to a significant decrease in agonist-promoted phosphorylation, β-arrestin binding, and endocytosis of S339fs5 and R334X compared to wild type CXCR4. Interestingly, there were also significant differences in receptor degradation, with S339fs5 having a very high basal level of degradation compared to that of R334X and wild type CXCR4. In contrast to wild type CXCR4, both R334X and S339fs5 were largely insensitive to CXCL12-promoted degradation. Moreover, while basal and agonist-promoted degradation of wild type CXCR4 was effectively inhibited by the CXCR4 antagonist TE-14016, this had no effect on the degradation of the WHIM mutants. Taken together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, that promotes enhanced signaling, reduced phosphorylation, β-arrestin binding and endocytosis, and a very high basal rate of degradation that is not protected by antagonist treatment. Read full article

Self-docking and cross-docking simulations of G protein-coupled receptor-ligand complexes: Impact of ligand type and receptor activation state G protein-coupled receptors (GPCR) are the largest family of cell surface receptors in vertebrates. Their abundance and role in nearly all physiological systems make GPCR the largest protein family targeted for development of pharmaceuticals. Ligand discovery aimed at identification of chemical tools and drug leads is aided by molecular docking simulations that allow critical analysis of the potential interactions between small molecules and proteins in resulting complexes. However, blind assessments of ligand pose quality and affinity prediction have thus far not provided broadly generalizable performance expectations for docking into experimentally-characterized GPCR targets. Likewise, the relative importance of receptor activation state and ligand function differences have also not been systematically assessed. This study compares performance when docking ligands of varied function into varied GPCR activation states in the absence of extensive resampling of the input GPCR structure, and only limited sidechain flexibility after ligand placement. Simulations were performed using 37 experimental structures of 11 Class A GPCR crystallized in multiple activation states (giving rise to 37 self-docking and 68 cross docking simulations). Our results show that one specific subset of cross-docking simulations gave results of similar quality to self-docking. Median ligand RMSD values for top-scored poses were 1.2 Å and 2.0 Å for self-docking and StateMatch/FunctionMatch cross-docking, respectively. The distributions of ligand RMSD values were not statistically different for these two conditions, according to a Kolmogorov-Smirnov test. Therefore, docking performance against GPCR targets can be estimated in advance based on docking target structure activation states, with higher accuracy expected when docking agonists into active state structures and inverse agonists or antagonists into inactive state structures. Receptor conformational sampling in advance of docking or receptor conformational adjustment after docking are more likely to produce substantial improvements for other pairings of receptor activation state and ligand function. Read full article