Starlight’s Post

Here’s another gem from Derek Lowe's "In the Pipeline" series. An imagined 1990s dialogue between a Section Head and a Bench Chemist in med-chem captures how revolutionary bifunctional molecules for protein degradation might have seemed. First validated in 2001 and boosted by 2012 VHL ligand discoveries, this concept faced skepticism and challenges. Fast forward, bifunctional protein degraders entered clinical trials in 2019, and now, over 18 targeted degraders, including PROTACs and molecular glues, are being tested. Article: https://lnkd.in/gBamMpQ7 #DrugDevelopment #ProteinDegradation #ClinicalTrials

Which Lipid Nanoparticle (LNP) Designs Work? A Simple Kinetic Model Linking LNP Chemical Structure to In Vivo Delivery Performance "A simple kinetic model was developed by using major rate-limiting steps for siRNA delivery, and this model enabled the identification of a critical parameter to predict LNP efficacy without extensive experimental testing. A volume-averaged log D, the “solubility” of charged molecules as a function of pH weighted by component volume fractions, resulted in a good correlation between LNP composition and siRNA delivery. Both the effects of modifying the structures of ionizable lipids and LNP composition on gene silencing were easily captured in the model predictions. Thus, this approach provides a robust LNP structure–activity relationship to dramatically accelerate the realization of effective LNP formulations." Esther H. Roh, Millicent O. Sullivan, and Thomas H. Epps III. ACS Applied Materials & Interfaces 2024 16 (11), 13399-13410. #LNP #nanoparticles

They write: Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5–MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5–MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.

If you're looking for improved ways to characterize your lipid nanoparticles (LNPs), join me for a webinar on analytical ultracentrifugation (AUC) and how it can help analyze several of your CQAs in a single experiment. The webinar will also examine AUC's ability to characterize RNA. It can determine purity and oligomerization states and whether multiple folding states are present, which could affect its stability and function.

Anyone working with lipid nanoparticles? Would you like to know more about your sedimentation and diffusion coefficient distributions of the LNPs, as well as the lipid and RNA components and fill rates? Register to learn what analytical ultracentrifugation can do for you.

Inflammation modulation: simultaneous target validation and hit finding using a chemo-proteomic approach on SLC15A4. Using a similar methodology to that used to target transcription factors, (https://lnkd.in/d_uPQU7X), another team from the chemistry Dpt. of the Scripps Research Institute, now shows engagement and modulation of SLC15A4, a12-transmembrane (TM) domain protein. (Chiu et al.; Nature chem. biol.  January the 8th 2024). Their low µM compounds do bind SLC154A4 and inhibit the downstream functions responsible for inflammation. Here again, the compounds are clearly no drug yet. Nevertheless, this approach, as the authors rightly claim, allows robust target dentification, validation and experimental druggability assessment with the added benefits of providing chemical probes and even possibly starting points highlighting the strength of the method.   #drugdiscovery #inflammation #chemoproteomics #membraneprotein #slccarriers #ScrippsResearch #SLC15A4 Below: PDB  8WX5, Cryo-EM structure of human SLC15A4 in complex with TASL.

SelectBIO Extracellular Vesicles (EVs) & Nanoparticles 2024 kicked off yesterday in Miami, and Dr. Sven Kreutel and Kevin Dolan are all set up. If you didn't get a chance to attend Sven's talk on #NanoparticleTracking yesterday, stop by their booth today. They will be happy to explain how you can use #NTA to characterize #ExtracellularVesicles (#EVs), #exosomes and other biological material in the range of 30 nm to 1 µm in your lab. Find out more about classical NTA, the detection capabilities of F-NTA and the use of C-NTA to better understand the composition of #biomarkers on individual particles. See you there! #Diagnostics #Delivery #Therapeutics #nanoparticles #particlemetrix #ZetaView

Modified and unmodified oligonucleotides are efficiently separated and purified through ion pair reversed phase (IP-RP) separations. Downstream purification of oligos presents challenges due to a variety of reasons, for example impurities can be very similar to the target molecules. In this application note, we highlight the use of a batch-tested preparative column specifically designed for oligos, combined with HFIP-free mobile phase. This strategy provides a new level of assurance for the development of high throughput, high recovery purifications of CRISPR sgRNA, siRNA and oligo-conjugates. Read the application note here: https://bit.ly/3ZBZfCL

Find technologies and resources to deliver deeper insights, assessing drug performance and determining mechanism of action in a live, dynamic cellular environment. https://bit.ly/3xAuYsq #cellbiology#molecularbiology

In our latest publication, we explore the rediscovered paradigm of 𝗰𝗼𝘃𝗮𝗹𝗲𝗻𝘁 𝗶𝗻𝗵𝗶𝗯𝗶𝘁𝗶𝗼𝗻 to establish the foundation for an additional specific 𝗮𝗻𝘁𝗶𝗰𝗵𝗹𝗮𝗺𝘆𝗱𝗶𝗮𝗹 𝘁𝗵𝗲𝗿𝗮𝗽𝘆 by small molecules targeting 𝗱𝗲𝘂𝗯𝗶𝗾𝘂𝗶𝘁𝘆𝗹𝗮𝘀𝗲 𝗲𝗻𝘇𝘆𝗺𝗲𝘀 (DUBs). This was made possible through an iterative cycle of molecular docking, chemical synthesis, and enzymatic screening. Many thanks to my colleagues at The Julius Maximilians University of Würzburg that made this development possible! https://lnkd.in/dF_X2DZ9