Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation
Centre for Targeted Protein Degradation, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
https://doi.org/10.1038/s41589-026-02224-y
PROTACs often rely on a single E3 ligase to induce protein degradation. While there have been reports of PROTACs capable of recruiting two E3 ligases, the need for two ligase warheads significantly reduces their drug-like properties. In contrast, all reported molecular glue degraders rely on a single E3 ligase. In this work, the authors investigate molecular glues reported by Genentech in a 2023 patent. They discovered that degradation of SMARCA 2/4 was dependent on two E3 ligases, with DCAF16 acting as the primary degrader and FBXO22 as a secondary degrader. Through small modifications to the parent compound, the dependence can be switched between DCAF16 and FBXO22.
Disrupted molecular glue complex drives RAS inhibitor resistance
Sloan Kettering Cancer Center, Rockefeller University, Revolution Medicines, Dana-Farber Cancer Institute, New York University Langone Health, Virginia Cancer Specialists Research Institute, University of Utah, MD Anderson Cancer Center, Weill Cornell Medical College
https://doi.org/10.1016/j.cell.2026.03.031
Daraxonrasib is one of the hottest molecules in drug discovery right now. Results from the phase 3 RASolute trial showed the drug doubled survival time for patients with pancreatic cancer when compared to chemotherapy. This article describes the resistance mechanisms to this class of compounds. Mutations to Y64 and Y71 of KRAS result in a decrease in binding between daraxonrasib-KRAS, or an increase in KRAS-RAF binding. Kinase-dead or hypoactive BRAF mutations were also found to lead to resistance.
Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR
Merck’s PCSK9 inhibitor enlicitide reshaped how chemists thought about oral bioavailability in the beyond rule of 5 chemical space. Phase 3 results indicate that it achieves comparable reductions in LDL-C levels as injectable antibody inhibitors, despite being ~1/100th of their molecular weight. This paper highlights the development process behind enlicitide, including the modular synthesis, which allowed for rapid DMTA cycles.
The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers
Tango Therapeutics
https://doi.org/10.1021/acs.jmedchem.6c00035
This is the latest in a series of papers from Tango Therapeutics discussing the development of their PRMT5 inhibitors. During the preclinical development of TNG908 and vopimetostat, it became clear that the selectivity and CNS exposure of these molecules could limit their use. This article describes the optimisation of compounds based on an aminopyrazolopyridine core. This led to the development of TNG456, which is currently being evaluated in phase 1/2 clinical trials for the treatment of advanced or metastatic solid tumours with MTAP loss.
Discovery and Optimization of Potent and Subtype-Selective Urea-Derived NaV1.8 Inhibitors
Grünenthal GmbH
https://doi.org/10.1021/acsmedchemlett.6c00130
Vertex’s NaV1.8 inhibitor suzetrigine was approved in January 2025 and marked a significant advancement in nonopioid pain management. This article displays Grünenthal’s efforts to discover their own NaV1.8 inhibitor. This started with a pharmacophore-filter-based virtual screen of ~25 million compounds. Refinement of the virtual screen output led to a sub-micromolar urea-based hit. Optimisation led to a compound with a long in vivo half-life and high exposure and represents a promising starting point for further optimisation.