Alexis Labrador’s Post

PROTAC's not the only degrader in town!      While PROTACs (proteolysis-targeting chimeras) are well-established as powerful tools for targeted protein degradation, here are some lesser-known technologies that have expanded the degrader toolbox in recent years:      LYTACs: lysosome-targeting chimeras that leverage the endosome-lysosome pathway to degrade extracellular and membrane proteins  AUTACs: autophagy-targeting chimeras that trigger lysosome-mediated degradation through the autophagy-lysosome pathway  ATTECs: autophagosome-tethering compounds that induce autophagic degradation of a target protein  AbTACs: antibody-based PROTACs that facilitate lysosomal degradation of cell-surface proteins  GlueTACs: PROTAC-based strategies that use GlueBody covalent nanobodies to promote lysosomal degradation of cell-surface targets      As the PROTAC alphabet expands, so do the possibilities for clinical application. These diverse protein degradation strategies enable the effective degradation of an increased range of cellular targets with more flexibility than ever before. We can't wait to see how these technologies continue to develop and transform the therapeutic landscape!      Zhao et al. Sig Trans Targ Therapy 7, 113 (2022)  Cotton et al. J Am Chem Soc 143, 593-8 (2021)   Zhang et al. J Am Chem Soc 143, 16377-92 (2021)  Banik et al. Nature 584, 291-7 (2020)  Li et al. Autophagy 1, 185-7 (2019)  Takahashi et al. Mol Cell 76, 797-810 (2019)    #PROTAC #LYTAC #AUTAC #ATTEC #AbTAC #GlueTAC #DrugDiscovery #MedicinalChemistry 

The Nature article published on May 8, 2024, by Nuria Díaz, Laura Michael and colleagues from Eli Lilly and Company, unveils the discovery of Muvalaplin (LY3473329), the first selective oral therapy for lowering lipoprotein(a) [Lp(a)]. Lp(a), a cardiovascular risk factor, is a low-density lipoprotein (LDL)-like lipoprotein with apolipoprotein(a) [Apo(a)] bonded to apolipoprotein B100 [ApoB-100]. The study identified compounds capable of inhibiting Lp(a) formation with subnanomolar potency by inhibiting the initial step of Lp(a) formation. This step involves binding to the kringle IV 7 and 8 domains (KIV7 and KIV8) of Apo(a) to prevent its interaction with lysine-rich regions of ApoB-100. Through chemical optimization and multivalency strategies, the authors developed Muvalaplin (LY3473329), a potent disruptor that significantly reduced Lp(a) levels in animal models without affecting plasminogen activity. https://lnkd.in/gb5v9EWx Meanwhile, Stephen Nicholls-led phase I study published in JAMA on September 19, 2023, demonstrated the safety and efficacy of muvalaplin. The study showed dose-dependent increases in plasma concentrations without significant adverse effects. Notably, muvalaplin lowered Lp(a) levels by up to 65% following daily oral administration for 14 days, without notably impacting plasminogen activity. https://lnkd.in/gnSgAQdw Phase 2 studies (NCT05563246) of Muvalaplin (LY3473329) were completed in March 2024. https://lnkd.in/grMemsmj The discovery of muvalaplin represents a promising therapeutic approach for lowering elevated Lp(a) levels and reducing residual cardiovascular risk through its novel mechanism of selectively inhibiting Lp(a) particle formation. #Muvalaplin #LY3473329 #Lp(a) #lipoprotein(a) #pelacarsen #olpasiran #lepodisiran #Zerlasiran #Atherosclerosis #ASCVD

Targeted protein degraders (TPDs) are a rapidly evolving class of drugs with great promise for addressing difficult drug targets. TPDs, including molecular glues and heterobifunctional degraders, utilize endogenous protein degradation processes to target previously 'undruggable' sites and a diverse array of therapeutic protein targets. This symposium will discuss the nonclinical and translational safety assessment of heterobifunctional degraders (often called proteolysis targeting chimeras or PROTACS) and molecular glues, focusing on the key challenges of early de-risking, nonclinical species selection, and clinical translation. Register for the Annual Meeting here: https://lnkd.in/ek5UQRza

In PK studies, special administration methods may increase drug concentration in the target tissue, enhance therapeutic effects, or reduce the incidence of adverse reactions. Yufeng Meng, the Assistant Director of #DMPK at Medicilon, provides insights on the techniques and applications of target organ biopsy in PK studies. This information aims to help reduce confusion and challenges in #PK trials.

In PK studies, special administration methods may increase drug concentration in the target tissue, enhance therapeutic effects, or reduce the incidence of adverse reactions. Yufeng Meng, the Assistant Director of #DMPK at Medicilon, provides insights on the techniques and applications of target organ biopsy in PK studies. This information aims to help reduce confusion and challenges in #PK trials.

I am excited to announce the publication of my latest paper titled "A Lipid-Based Delivery Platform for Thermo-Responsive Delivery of Teriparatide". https://lnkd.in/e4U3XExa   This work was a key part of my PhD research and a project I’ve been deeply passionate about. Herein we develop thermo-responsive teriparatide loaded liposomes as a potential pulsatile delivery system.   Key points of our research include: 📌 Hydrophobic ion pairing of teriparatide enhances peptide entrapment within liposomes 📌 Providing a first proof-of concept demonstrating the suitability of thermo-responsive liposomes as pulsatile delivery system 📌 Development of a cell-based receptor-binding assay to demonstrate retention of teriparatides biological activity   I'm very grateful to my co-authors for their support and contributions throughout this project: Wojciech Rozek, Ryan Mellor, Szymon W. Manka, Chris Morris, Steve Brocchini, and Gareth Williams.   #peptides #teriparatide #themoresponsive #liposomes #pulsatile #controlledrelease #DrugDelivery #PhD #cdt #research

JAKA Biotech (GREAF) demonstrates the anti-ageing effects of Bifida Ferment Lysate, which were validated by in vitro and clinical efficacy tests. The results indicate that Bifida Ferment Lysate effectively inhibits cellular senescence and delays the formation of wrinkles.

This paper pick from scientists at Novartis describes the human ADME characteristics of icenticaftor and its major circulating glucuronides. Several interesting elements are discussed in the paper and highlighted here including the appearance of a third major glucuronide during the human ADME study. Also worth noting was the non-linear PK observed after administration of single & multiple doses, proposed to be due to saturation of UGT1A9. Read more at https://lnkd.in/gMf9QvGc #drugmetabolism #glucuronide

Do you have a good story to tell regarding oxidative defluorination metabolism on saturated or unsaturated systems? Was it specific to one species? Did the in vitro hepatocyte met ID data mirror in vivo met ID? Really interested in this mode of oxidative metabolism, and would love to see more examples of this published in JMC. With the significant increase in fluorinated compounds in drug discovery, we need more attention on the C-F bond as a metabolic issue and not always a panacea. #JMEDCHEM

🌟 Exciting Highlights from the 3rd LNP Immunogenicity and Toxicity Summit! 🌟 We are delighted to share that our Founder and CEO, Dr. Bin Wu, presented Cytodigm's pioneering work on "PEG-free" lipid nanoparticles (LNPs) at the recent summit in #Boston. In his presentation, "Case Study: Building Next-Generation LNPs with Gangliosides Instead of PEG-Lipid to Reinvent Safety & Mitigate Immunogenicity," Dr. Wu introduced our innovative #Cytofinity™ #LNP technology. This advanced platform incorporates ganglioside, a natural and endogenous lipid, as opposed to PEG-lipid, a key component in traditional LNPs, to eliminate PEG-mediated immunogenicity. Besides being PEG-free, Cytofinity™ also stands out with its remarkable ability to target extrahepatic tissues and cells without needing antibody conjugation. Cytofinity’s diverse formulations can effectively deliver RNAs to the lung, bone marrow, T cells, and HSCs, broadening possibilities in nucleic acid-based therapies. We are excited about the transformative impact of Cytofinity™ and look forward to exploring more opportunities to collaborate and innovate! #Innovation #Biotech #Drugdelivery #Lipidnanoparticle #Biotechnology #Nanotechnology #Therapeutics #DDS #immunogenicity #Biotechinnovation