Kassoum Nacro

Multivalency Key to a Potential First-in-Class Lp(a) Formation Inhibitor | https://lnkd.in/gEVeTc32 Eli Lilly and Company's muvalaplin (LY3473329) is the first selective, oral small molecule Lp(a) (lipoprotein(a)) formation inhibitor to enter the clinic. Mulvalaplin disrupts the formation of Lp(a), an established, genetically-determined risk factor for cardiovascular disease, by binding to multiple kringle domains of the precursor apo(a) protein through its trimeric structure. Eli Lilly recently announced positive results from its Ph. II study in adults with elevated Lp(a) levels, demonstrating dose-dependent reduction in Lp(a) levels with few adverse events. Read the story behind the compound on Drug Hunter | https://lnkd.in/gEVeTc32

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Bayer Discloses its Selective Dual Factor IIa/Xa Inhibitor, BAY 3389934 | https://lnkd.in/gXYKknNv BAY 3389934 is a potent and selective small molecule dual factor IIa/Xa inhibitor, currently in Ph. I for the treatment of SIC (sepsis-induced coagulopathy). This small molecule was designed as a “soft drug”, featuring a metabolically labile carboxylic ester, that accounts for its short-acting anticoagulant effects and strong safety profile. In this molecule profile, we highlight the key structural features behind Bayer | Pharmaceuticals' discovery of BAY 3389934 as a nanomolar-potent, highly soluble compound designed for i.v. administration. Read it on Drug Hunter | https://lnkd.in/gXYKknNv

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Covalent inhibitors, degraders, macrocycles... 12 new drug disclosures show where medicinal chemistry is heading these days 👇 Just finished reading a great piece by Bethany Halford in C&EN called “12 drug candidates debut in San Diego”, summarizing the "First-Time Disclosures" session at ACS Spring 2025. The chemistry behind many of these is genuinely impressive, but I also wanted to share some quick observations I think are interesting: 1. Several candidates were engineered to distinguish between closely related targets, e.g. PRT3789 selectively degrades SMARCA2 over SMARCA4, and IAMA-6 was designed to avoid NKCC2 while engaging NKCC1. Achieving this kind of fine-tuned selectivity required thoughtful structure-based design, especially when targeting conserved protein families. 2. Irreversible and degradation mechanisms were featured prominently. Among these 12 molecules, a few use covalent binding (e.g., PF-07853578, ORIC-114) or induce targeted degradation (e.g., PRT3789, BMS-986458). While these approaches are not necessarily dominant across the field, they’re clearly gaining visibility and being applied to challenging or previously “undruggable” targets. 3. The disclosures included macrocyclic peptides, FBDD-derived metal binders, and PEG-fatty acid conjugates, alongside more traditional small molecules. These structural choices often addressed specific needs, like improving half-life, selectivity, or target engagement, not just novelty for its own sake. 4. Two compounds, ORIC-114 and IAMA-6, demonstrated blood-brain barrier penetration, an important but challenging property for CNS-active drugs. IAMA-6 was explicitly designed for CNS exposure, while ORIC-114 showed unexpected permeability despite its structure, highlighting different paths to achieving brain penetration. 5. A few teams highlighted their development workflows. For example, Repare Tx focused on improving ADME properties before optimizing potency for RP-1664, and AstraZeneca applied AI-based scaffold selection for AZD2389. 6. Focus on novel biological targets... Indeed, many of the candidates aim at underexplored targets such as PLK4, PNPLA3 I148M, and FAP. That’s not necessarily reflective of the entire pipeline across pharma, but it’s consistent with the spirit of the conference, so was expected. 7. Oncology still dominates (who would know?). Half of the disclosures target oncology indications. The rest span neurological disorders, liver disease, infections, cardiovascular dysfunction, and sepsis. I think is not a shock and pretty much in line with industry-wide pipelines... oncology is a lucrative field. Anyway, fellow chemistry fans, your thoughts? Image credit: C&EN

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🔬 𝐎𝐥𝐢𝐠𝐨𝐧𝐮𝐜𝐥𝐞𝐨𝐭𝐢𝐝𝐞 𝐓𝐡𝐞𝐫𝐚𝐩𝐞𝐮𝐭𝐢𝐜𝐬: 𝐀𝐧𝐚𝐥𝐲𝐭𝐢𝐜𝐚𝐥 𝐂𝐡𝐚𝐥𝐥𝐞𝐧𝐠𝐞𝐬 𝐚𝐧𝐝 𝐀𝐝𝐯𝐚𝐧𝐜𝐞𝐬 𝐢𝐧 𝐃𝐢𝐚𝐬𝐭𝐞𝐫𝐞𝐨𝐦𝐞𝐫 𝐂𝐡𝐚𝐫𝐚𝐜𝐭𝐞𝐫𝐢𝐳𝐚𝐭𝐢𝐨𝐧 🧬 Phosphorothioate (PS)-modified oligonucleotides—central to ASOs and siRNAs—introduce chiral complexity that manifests as vast mixtures of diastereomers. While enhancing nuclease resistance, these modifications complicate analytical characterization, especially for highly modified constructs like Nusinersen, with >130,000 diastereomers. 📈 Over the past two years, the field has seen rapid development in state-of-the-art techniques aimed at deciphering this complexity, driven by increasing regulatory expectations from FDA and European Medicines Agency, and recent funding calls by the NIH. 💡 𝐊𝐞𝐲 𝐚𝐧𝐚𝐥𝐲𝐭𝐢𝐜𝐚𝐥 𝐬𝐭𝐫𝐚𝐭𝐞𝐠𝐢𝐞𝐬 𝐢𝐧𝐜𝐥𝐮𝐝𝐞: 1️⃣ 𝐿𝑖𝑞𝑢𝑖𝑑 𝐶ℎ𝑟𝑜𝑚𝑎𝑡𝑜𝑔𝑟𝑎𝑝ℎ𝑦 • IPRP and AEC remain gold standards, but recent advances in HILIC show promise, particularly under non-denaturing conditions and with LNA-containing constructs. • A 2025 study achieved partial resolution of 32 diastereomers using 2D-LC (Chiral × RPLC), the current upper limit. 2️⃣ 𝐼𝑜𝑛 𝑀𝑜𝑏𝑖𝑙𝑖𝑡𝑦 𝑀𝑎𝑠𝑠 𝑆𝑝𝑒𝑐𝑡𝑟𝑜𝑚𝑒𝑡𝑟𝑦 • Emerging as a powerful tool for shape-based separation, especially effective for short oligonucleotides. • Cyclic IM-MS enables multi-pass separations and can resolve up to 8 diastereomers in 36-mer constructs. 3️⃣ 𝐸𝑛𝑧𝑦𝑚𝑎𝑡𝑖𝑐 𝐷𝑖𝑔𝑒𝑠𝑡𝑖𝑜𝑛 • Reduces analytical complexity by selectively cleaving at Sp or Rp configurations, enabling fingerprinting and batch comparability for high-PS-content oligonucleotides. 4️⃣ 𝐶𝑎𝑝𝑖𝑙𝑙𝑎𝑟𝑦 𝐺𝑒𝑙 𝐸𝑙𝑒𝑐𝑡𝑟𝑜𝑝ℎ𝑜𝑟𝑒𝑠𝑖𝑠 Separation driven by hydrophobic interactions with sieving matrices like PVP. Interestingly, rigid sugar modifications (e.g., LNA) impair CGE but enhance HILIC separation. 📌 While significant progress has been made, challenges remain in stereochemical assignment (Sp vs Rp) and achieving higher resolution beyond the 32-diastereomer threshold. Future work may leverage online multi-dimensional LC-MS, immobilized nucleases, or enhanced stereopure marker synthesis for comprehensive characterization. 🎯 𝐊𝐞𝐲 𝐓𝐚𝐤𝐞-𝐀𝐰𝐚𝐲𝐬: • PS-modified oligonucleotides can generate thousands of diastereomers, demanding sophisticated analytical tools 🧪 • LC remains the cornerstone technique, with RPLC, IPRP, HILIC and AEC offering complementary insights 📊 • IM-MS and CGE provide shape- and size-based separation modes with growing potential 🚀 • Enzymatic digestion is critical for simplifying complexity in long or fully PS-modified sequences 🔍 • Regulatory agencies now expect diastereomeric fingerprinting and reproducibility data for therapeutic oligonucleotides ✅ #AnalyticalSciences #Oligonucleotides #Diastereomers #Phosphorothioate #Chromatography #MassSpectrometry #NucleicAcidAnalysis Alexandre Goyon, Daniel Nguyen & Kelly Zhang / Genentech

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University of Delaware chemical and biomolecular engineer Cathy Fromen is reimagining the role of immune cells called macrophages—think of them as the lung’s frontline guards — in the fight against cancer. Fromen is developing a kind of “boot camp” to train these cells to hunt down lung cancer, in a nonsurgical way. Her work could revolutionize cell therapy far beyond the lungs. As an Innovation Ambassador at UD, Fromen is eager to share her experience as an inventor with others: https://brnw.ch/21wXvcI

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👉 Ready to source synthetic DNA with confidence? We’re excited to share a comprehensive new guide that explores how enzymatic DNA synthesis is rewriting the playbook for sequence complexity, speed, and accuracy. 🧬 Discover the latest advancements, from traditional chemical techniques to breakthrough enzymatic synthesis, accelerating research like never before. 💡 Learn about applications in drug discovery, cell and gene therapy, agricultural biotech, and sustainable biomanufacturing. 🔎 Uncover the key factors to consider when selecting your synthesis partner. 🧭 Navigate decisions that keep your research moving forward, free from delays caused by technology or supply chain issues. Download the guide now: https://lnkd.in/gZy2urBZ #SyntheticDNA #DNAsynthesis #longDNA #complexDNA #synbio #SynthesisWithoutStress

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Unlocking the Power of Glycan Recognition Discover how lectins, antibodies, and carbohydrate-binding modules (CBMs) are revolutionizing glycan analysis and advancing cancer research. In her article, Shuhui Chen, PhD from the Vector Laboratories team explores the cutting-edge world of glycan-binding proteins — from plant lectins to engineered recombinant tools — and how they’re shaping the future of diagnostics and therapeutics. Dive into the science of glycobiology and learn how these probes are transforming our understanding of disease. Read the full article on the Vector Labs website: #Glycobiology #Lectins #CancerResearch #Immunohistochemistry #Immunofluorescence

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Alnylam’s $250M production investment (aka... oligos, oligos, oligos)... Enzymatic oligo synthesis is top of mind across the market. Everyone is working on it, from Codexis to Hongene to a growing list of CDMOs. But enzymatic approaches are not universally cheaper. As of now, they have the potential to be cheaper than chemical methods ONLY at very high volumes. Alnylam is one of the few companies where that math works, thanks to real commercial traction and ambitions in common diseases like hypertension, diabetes, and obesity. Meanwhile, solid-phase oligo synthesis is far from dead. Agilent has built up their capacity over the years and is still bullish on filling it. Why? Most approved oligo drugs and late-stage pipelines are still rare disease or specialty indications, where manufacturing processes do not change mid-lifecycle and volumes remain well suited to solid-phase chemistry. Even enzymatic workflows still depend on chemically synthesized inputs. The bigger story is that everyone forgot about oligos during the pandemic. While mRNA dominated headlines, the oligo modality quietly kept growing (I know we see this in our proprietary asset tracker, TheraTrack). This feels a lot like peptides. Solid-phase synthesis dominates today, while enzymatic or recombinant approaches emerge only where scale truly demands it. The real question is when to invest (and how) in one or the other. For biopharma, CDMOs, and suppliers, the strategic challenge now is deciding where to place bets: which segments will actually drive growth, where scale changes the economics, and how to position offerings before the market consensus shifts. That is where the next wave of value will be created in oligos. If you’re making manufacturing, capacity, or platform bets in oligos right now, this is a moment worth pressure-testing assumptions. #biotech #pharma #genetherapy

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Our very own Paraskevi Gkeka and colleagues recently published a thoughtful perspective on the evolution of computational hit finding in the Journal of Medicinal Chemistry. From the earliest days of manually screening thousands of compounds, through the rise of vast physical libraries, we’re now entering a transformative era: leveraging AI-driven, cloud-enabled virtual screening to rapidly explore billions of molecules. This shift dramatically improves efficiency, reduces wasted effort, and, crucially, accelerates delivery of new medicines to patients. A great read capturing both the history and future promise of this field: https://lnkd.in/eviPUP_y #DrugDiscovery #VirtualScreening #AI #ComputationalChemistry Paraskevi (Evi) Gkeka

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