Gain Therapeutics’ Post

I am pleased to share insights from our recent review article, which explores the advancements in Proteolysis Targeting Chimeras (PROTACs)—a revolutionary approach in Target Protein Degradation (TPD). In an era where numerous disease-causing proteins remain undruggable due to structural intricacies, PROTACs are demonstrating remarkable promise as a transformative tool in drug discovery. 🔬 What Are PROTACs? PROTACs are small, multifunctional molecules designed to facilitate the degradation of harmful proteins rather than merely inhibiting their activity. These unique molecules function by recruiting the protein of interest (POI) and an E3 ligase, thereby initiating the poly-ubiquitination process and effectively marking the POI for degradation via the ubiquitin-proteasome system (UPS). 🌐 Our Key Focus: Designing Optimal Ternary Complexes Through the application of advanced in-silico and biochemical methodologies, we investigated strategies for optimizing ternary complexes, a pivotal factor in the successful functioning of PROTACs. Our review underscores the significance of ligand selection, linker design, and computational approaches, all of which are essential for the formation of stable and cooperative ternary complexes. 💡 Why This Matters The therapeutic potential of PROTACs is substantial, with over 20 candidates currently undergoing clinical trials for conditions spanning from cancers to autoimmune diseases. This research endeavours to address the challenges associated with the stability, selectivity, and efficiency of PROTACs, thereby advancing our ability to develop effective treatments for previously untreatable diseases. Many thanks to Shareef Shaik and Professor Aravinda Pai for giving me this opportunity to be part of this informative review. 📘 Learn More For those seeking a comprehensive understanding of the scientific underpinnings, our article delves into intricate mechanisms, cutting-edge methodologies, and the pivotal role of linkers in stabilizing the ternary complex. By optimizing these factors, we aspire to accelerate the discovery of more efficacious PROTAC therapies. #DrugDiscovery #ProteinDegradation #PROTACs #TargetedTherapies

Featured ArticleSeptember 23, 2024 Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader Atsunori KaneshigeYiqing YangLongchuan BaiMi WangRenqi XuLeena MallikKrishnapriya ChinnaswamyHoda MetwallyYu WangDonna McEachernJelena TošovićChao-Yie YangPaul D. KirchhoffJennifer L. MeagherJeanne A. StuckeyShaomeng Wang* STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with Ki = 3.5 μM binding affinity, we obtained AK-068 with Ki = 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50 values of as low as 1 nM while showing minimal effect on other STAT members up to 10 μM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization. This publication is licensed for personal use by The American Chemical Society. © 2024 American Chemical Society

Identifying potential compounds from Bacopa monnieri (brahmi) against coxsackievirus A16 RdRp targeting HFM disease (tomato flu) https://lnkd.in/gnfhSWiu #MedTwitter #scicomm #MedEd #AcademicTwitter #RNA-Dependent #RNA polymerase #Hand #Foot Study finds RdRp inhibitors as potential treatments for HFMD caused by Coxsackievirus A16. 91 Bacopa monnieri compounds screened against CVA16 RdRp. Bacobitacin D showed significant interaction with RdRp. Molecular Dynamics simulation and ΔGTOTAL calculations were achieved on top three hits. Bacobitacin D was identified as active inhibitor against CVA16 RdRp. #innovation #tecnology #research

siRNAs for cardiovascular disease?! 🧬 I recently studied up on this and wanted to share some of my most salient notes. 📝 20% of the population has elevated lipoprotein A levels - Lp(a), which presents a risk factor for cardiovascular problems. Lp(a) is plaque forming, and it makes problematic types of lipid carriers, which are similar to but different than #LDL-cholesterol. ⚕️It is now suggested that a good majority of atherosclerotic cardiovascular disease is not driven by LDL-cholesterol but instead genetically elevated Lp(a), which cannot be modified much by adapting diet and exercise. 📉 #Lepodisiran from Eli Lilly and Company #Olpasiran from Amgen, and #Zerlasiran from Silence Therapeutics plc have shown impressive clinical results to give long duration reductions in LpA levels. Each uses #GalNAc conjugates for efficient uptake by the liver. The molecular design of each is unique, though. I’ve compiled some of my #siRNA pharmacology and molecular structure notes in the attached Figure. Perhaps this wave of pipeline success and molecular design will intrigue you too. Olpasiran (Amgen): Phase 3 started Dec 2022. Lepodisiran (Lilly): Phase 3 started Mar 2024. Zerlasiran (Silence): Phase 2 ending soon. 📊Efficacy + Dosing Durability: https://lnkd.in/ekxMHbfe #biotech #CGT #GTx #oligonucleotides #PKPD #ADME #HPLC #LCMS ————————— I’m Matt Lauber - an analytical biochemist who loves separating biomolecules, detecting masses, and all things biotechnology! ☑️ Follow & subscribe 🔔

Human serum albumin (HSA) revolutionizes #healthcare with its diverse applications in #drugdelivery, #diagnostics, and #biotechnology. Advances in structural biology enhance its efficacy in targeting diseases, improving drug delivery systems, and developing diagnostic assays, showcasing HSA's potential in transforming medical and industrial fields. #RDive #HumanSerumAlbumin #HSA #MedicalInnovation #DrugDelivery #Diagnostics #Biotechnology #HealthcareAdvancements #Biocompatibility #PharmaceuticalResearch #ChronicDiseaseTreatment #StructuralBiology #Proteomics #TherapeuticApplications #BiomedicalResearch https://lnkd.in/dxjZz5bw

Happy to share our recent paper " Investigating the Impact of IL6 on Insulin Secretion: Evidence from INS-1 Cells, Human Pancreatic Islets, and Serum Analysis". in MDPI-Cell. The study investigates the role of Interleukin-6 (IL6) on insulin secretion and glucose metabolism using a series of functional and molecular experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key β-cell genes in both INS-1 cells and human islets.

𝐑𝐞𝐜𝐞𝐧𝐭 𝐃𝐞𝐩𝐚𝐫𝐭𝐦𝐞𝐧𝐭 𝐨𝐟 𝐏𝐡𝐚𝐫𝐦𝐚𝐜𝐨𝐥𝐨𝐠𝐲 𝐏𝐮𝐛𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬: June and July Are you interested in keeping up with the latest publications from the Department? We have compiled all the publications released in June and July for your reading pleasure. You can find an RSS feed of our publications here: https://lnkd.in/eD2nmgjJ Dissecting the roles of dynamin and clathrin in platelet pinocytosis - Harper Group- https://lnkd.in/e56g2EUC Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights - St John Smith Group - https://lnkd.in/eaZVGd8t α-Synuclein Oligomers Displace Monomeric α-Synuclein from Lipid Membranes - Kumita Group - https://lnkd.in/eRN2zZiA Can Current Molecular Docking Methods Accurately Predict RNA Inhibitors? - Rahman Group - https://lnkd.in/e5RRENuB #Publications #Research #Pharmacology #Cambridge

🚨 New Publication Alert! 🚨 We are excited to share our latest research exploring the effect of 10 different size-exclusion chromatography (SEC) columns on plasma extracellular vesicle (EV) recovery, purity, and downstream miRNA analysis. Our findings raise an important question: Are we truly looking at EV-associated miRNAs in our analyses? These insights have critical implications for EV-miRNA biomarker research, where accurate miRNA profiling is essential for developing reliable diagnostic and therapeutic tools. 🔍 If you’re involved in EV research or EV-miRNA analysis, dive into our work to learn more about the importance of selecting the right SEC column. A big thank you to our incredible team and collaborators for making this possible! #ExtracellularVesicles #miRNA #Biomarkers #IZON #SEC #EVResearch #EVCNA Izon Science NLSEV - Netherlands Society for Extracellular Vesicles International Society for Extracellular Vesicles

Thrilled to share our latest research paper, where I am the first author, published in a Biomedicine Q1 journal (IF=3.9) on a novel Escherichia coli phage! This discovery has the potential to revolutionize the fight against antibiotic-resistant E. coli infections. I'm excited to see the impact of this work on the future of healthcare. Learn more about how this breakthrough could change the landscape of antimicrobial resistance. Click the link below to read the full article. #science #research #phagetherapy #antimicrobialresistance #microbiology  https://lnkd.in/dgwwEtgH

🔬Unlocking Insights into Fibrosis: The FMT Assay This assay provides critical insights into fibrotic diseases, outlining the importance of using culture conditions that promote controlled fibroblast activation and matrix deposition for accurate protein detection and quantification results. 🔍 A comprehensive set of data from a functionally validated high-throughput high-sensitivity FMT assay can: ✔️Accelerate your drug discovery by understanding compound efficacy against fibrosis through the evaluatin of up to 4 parameters across multiple donors ✔️Rapidly screen a library of compounds with high-throughput 384-well un-biased high-content imaging ✔️Capture minute changes in fibrotic marker expression that are critical in gauging anti-fibrotic drug efficacy with laser-based imaging and quantification Learn more here: https://lnkd.in/ePdxzcZm #NewcellsBiotech #Lung #FibrosisResearch #FMT