Geoff Muckle’s Post

Drug discovery for molecular glues in the last few years has largely been driven by the desire to identify degraders for target proteins, and while this remains an active field, glues with non-degrading properties are receiving more attention. NST-628, developed by Nested Therapeutics (Cambridge, MA), is a non-degrading molecular glue that promotes the interaction of A,B and C-RAF to MEK1. These complexes are inactive, and prevent signalling through the Ras pathway, which blocks downstream activation of ERK. NST-628 has good PK properties, and is brain penetrant, which is an opportunity to address cancer cells hiding out in the brain, potentially offering a treatment option for either primary or metastatic brain tumours. As reported by Ryan et al., (paper link below), the compound is well tolerated in pre-clinical in vivo models and leads to robust reduction in tumour growth. In combination with Sotorasib, low dose NST-628 show dramatic reduction in tumour growth, indicating that combination therapy could be promising. A phase 1 clinical trial for safety, PK and preliminary efficacy in adult patients with MAPK pathway mutated/dependent advanced solid tumours is currently ongoing for this novel non-degrading molecular glue. Link to paper: https://lnkd.in/dyA96mi8 Clinical trial: https://lnkd.in/dhQSc5KZ #TPD #drugdiscovery #innovation #molecularglue Figure adapted from published report

We look forward to introducing the PredicineCARE™ Ultra NGS data poster presentation in collaboration with Dana Farber Cancer Institute and Harvard Medical School on Day 1 of ASCO GI! Development and application of an ultra-sensitive ctDNA mutation profiling assay in monitoring therapy response and drug resistance    The highlights of this poster presentation include:    • Predicine has developed an ultra-sensitive NGS assay, PredicineCARE™ Ultra cfDNA Assay, to detect the low-frequency ctDNA mutants for monitoring therapy response and drug resistance. • PredicineCARE™ Ultra cfDNA Assay exhibited exceptional sensitivity (98.0% detection rate at a LoD down to 0.075% MAF) and high levels of specificity, precision and accuracy. • The addition of ~30% new low-frequency ctDNA mutants was detected compared to the standard ctDNA mutant profiling assay in a clinical trial for monitoring therapy response and drug resistance, indicating superior performance of the PredicineCARE™ Ultra cfDNA Assay in clinical applications.    Come and visit Booth #24 and discover our unique liquid biopsy solutions in support of global clinical trials, CDx development and commercialization. Schedule a meeting with the Predicine team:  https://lnkd.in/g8JK7vuc    Learn more about PredicineCARE™ Ultra and our other assays: https://lnkd.in/gS_-5H6f    #ASCOGI24 #precisiononcology #diagnostics #NGS #liquidbiopsy #mrd #ctdna #clinicaltrials 

A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models "Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. " "A key challenge in clinical translation is potentially dissimilar PK profiles generated in mice in comparison to humans, resulting in differences in target engagement profiles as well as off-target effects (4, 5). " excerpts from White, M.J., Cheatham, L., Wen, S. et al. A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models. AAPS J 25, 66 (2023). https://lnkd.in/gcFbVFxk https://lnkd.in/gJKfigPq #AZD5991 #clinicaltranslation #PKPD #preclinicalmodeling #translationalPK #vascularaccessbuttons #translationalresearch #preclinical

From in vitro to in vivo: Effective translation for anti-inflammatory treatments John Unitt, Vice President, Immunology and Inflammation Drug Discovery, at Sygnature Discovery, explores the importance of an effective translational process for preclinical and clinical success. https://lnkd.in/eMqChBfG #InVitro #InVivo #DrugDiscovery

We've been diving into some trends in current clinical trials for antibody-drug conjugates (ADCs), focusing particularly on the types of antibodies used and their target antigens. A review article by Edidiong U. et al. from the University of Illinois Chicago discusses over 500 active clinical trials investigating newer ADCs and addresses the challenges associated with their clinical translation. Here are some key points we found interesting: ➡️ Of all active clinical trials, only 36% focus on new ADCs. Interestingly, 90% of these new ADC trials target solid tumor applications, marking a significant shift from already approved ADCs. ➡️ 80% of trials target established antigens for hematological and solid tumors, including HER2 (32%), CD30 (14%), and TROP2 (9%). However, there is a growing interest in targeting novel antigens, which accounts for 20% of clinical trials. This push for novel antigens is likely driven by the expanding application of ADCs to solid tumors. Check out the article here: https://lnkd.in/gWEB9eZG #ADCs #AntibodyDrugConjugates #AntibodyTherapeutics #DrugDiscovery #AntibodyDiscovery

Will you be at Oxford Global’s Biomarkers Europe Congress in Berlin, Germany from Nov. 14-15? We’ll see you there! At the event, we’ll hear from and meet with leading experts in the biomarker space and learn how biomarker approaches empower oncology and immunotherapy drug development. Meet with us at the event to discuss our multiplex biomarker assays for tissue phenotyping and digital pathology. Ultivue’s new OmniVUE™ panels are configurable for the study of your biomarkers of interest and powered by our proprietary InSituPlex® technology that integrates into standard workflows. Learn how robust, repeatable results can accelerate your biomarker discovery and drug development programs. https://hubs.ly/Q0283nmV0 #Biomarkers23 #BiomarkerDiscovery #ImmunoOncology #Immunotherapy #ClinicalTrials #PrecisionMedicine #ImmuneProfiling

🎯Are you attending the Targeted Protein Degradation event of the year? The world's premier TPD meeting returns to Boston for 4 electrifying days of totally new content across 4 tracks bursting with first disclosures into preclinical and clinical degrader pipelines. ✔Your Own Copy of the Event Guide Awaits:  https://lnkd.in/e2z_TrcG Uncover how your peers are harnessing best-in-class platforms for degrader discovery, leverage the expertise of leading medicinal chemists optimizing compounds for maximum potency and efficacy, and explore the range of applications of TPD machinery beyond oncology, into immunology, CNS, extracellular space and beyond. Unite in Boston to explore how we create more potent, orally bioavailable, brain penetrant binfunctionals and molecular glues that harness systems beyond UPS to modulate targets of highest value. View all 95+ presentations here:  https://lnkd.in/e2z_TrcG

Explore the advanced applications of Nucleosome Quantification (Nu.Q®) technology for drug development and disease monitoring! This session features leading experts in epigenetics and assay development – Eric A. Ariazi, PhD, and Terry Kelly, PhD. Presentations will focus on the critical role of nucleosome-based markers in accelerating oncology clinical trials and enhancing drug efficacy and safety monitoring. Learn more & register here: https://bit.ly/3vLcdkX Key topics will include: ☑️ Next-generation epigenetic immunoassay for quantitative assessment of circulating nucleosomes ☑️ The role of Histone PTMs as biomarkers for chromatin-targeted therapies ☑️ Liquid biopsy applications in precision oncology ☑️ Expanding the utility of circulating nucleosomes to predict adverse reactions in therapy, including CAR-T cell treatment Thank you to Volition for making this webinar possible! #Immunoassay #Epigenetics #Genetherapy

Going to AMP 2023 in Salt Lake City, Utah? Stop by Booth #1011 for some goodies and learn from our team why our Oncology and PGx applications are used in molecular testing labs globally for solid tumor profiling and pharmacogenetics. Won’t be attending this year’s AMP? Skip the FOMO, and let us bring AMP to you! Register for either one of our workshops or both, and we’ll email you key takeaways and the recording to watch from your home. PGx Workshop: “From Data to Decisions: Advocating for DPYD Testing to Advance Patient Safety Based on Insights from Clinical Evidence,” presented by Victoria M. Pratt, PhD, FACMG, Director, Scientific Affairs for Pharmacogenetics, Agena Bioscience, and Prof. Dr. Ron H.N. van Schaik, PhD, FACB, register here: https://lnkd.in/gnQ5H_Hz  Oncology Workshop: “Rethinking Solid Tumor Profiling: How Utilizing Complementary Technologies can Allow Laboratories to Guide Better Treatment Decisions,” presented by Jessica S. Thomas, MD, PhD, MPH, register here: https://lnkd.in/gj-ZdngF To learn more about Agena at AMP, visit https://lnkd.in/gCEQyS5B. #AMP2023 #AssociationForMolecularPathology #MolecularPathology #Oncology #PGx #Pharmacogenomics #OncologyResearch #Pharmacogenetics #SolidTumorProfiling #biomarkerdetection

With the FDA and EMA approval of Updualag; the combo of PD-1 and Lag-3 blocking Abs, I think this beautiful paper needs another posting. Why?? Well, I think further dissemination of the data, would be helpful since in several even recent papers the mechanism of action of Lag-3 blockade is still discussed with a focus mainly on Hla Class II as the main ligand, and speculations focus on the lacking expression on cancer cells. Hla Class II is the first Lag-3 ligand described more than 30 years ago, and several other ligands have been suggested since. However, the paper by Guy et al., from the Vignali lab, provides some important info on the mechanism of action when it comes to Lag-3 blocking. Thus, it is very nicely shown that Lag-3 binds to the T cell receptor (TCR) on the T cell itself, i.e., in cis, and acts by hindering the CD4/8 co-stimulatory signal. Importantly, there is no need for a ligand on the target cell. Thus, the efficacy of Lag-3 blockade, of which numerous molecules are still in clinical testing, would most likely depend on blocking the interaction between the TCR and Lag-3. The clinical data from Updualag, although still early, suggests that it is as effective as the PD-1/CTLA-4 combo, but with milder side effects. If that is maintained as the data matures, that would pave the way for a more widely applicable combo, e.g., also potentially in the neo-adjuvant setting. Time will tell.  https://lnkd.in/dZ69EbEi