SyntheX has developed ToRNeDO, a cell-based platform that removes the reliance on serendipity in molecular glue and degrader discovery. It selects glues and degraders directly in living cells using defined target-ligase pairs, mapping novel degrons while bypassing the limits of in vitro assays and in silico methods. Using ToRNeDO, we discovered highly selective glues and degraders against previously untargeted proteins and E3 ligases, making discovery systematic and directed.

Molecular glue discovery beyond CRBN remains a major challenge. We established a target-agnostic VHL molecular glue discovery platform that integrates VHL-biased libraries with multiomics-based hit discovery, followed by rigorous hit validation and mechanism-of-action characterization using orthogonal cellular and biochemical assays. This approach identified dGEM3 and dCASP2, which recruit distinct structural degrons in GEMIN3 and caspase-2 to VHL, enabling selective ubiquitination and degradation while expanding the addressable VHL substrate landscape.

Targeted protein degradation is being explored as a strategy for bone regeneration beyond conventional growth factor-based approaches. This presentation will share our preclinical investigation of MDM2-targeting PROTACs, spanning cellular osteogenic assays and animal bone-defect models, including preliminary large-animal findings. We will discuss the evidence needed to link protein degradation to regenerative outcomes, alongside challenges in compound prioritization, local delivery, and species-dependent biology that shape translation toward regenerative medicine.

Zymoseptoria (Z.) tritici is a fungal phytopathogen that causes major foliar disease in wheat. We used activity-based protein profiling to generate a covalent ligandability map of Z. tritici, leading to the discovery of electrophilic small molecules that target a diverse set of essential proteins, including covalent ligands that engage an ortholog-restricted cysteine in the GTPase SAR1, leading to its aggregation with other COPII components and impairments in Z. tritici growth.

Our group is developing novel strategies for the targeted degradation of extracellular and membrane proteins. Recent advances include a degrader with the potential to cross the blood–brain barrier and degrade amyloid aggregates, as well as two distinct catalytic approaches for extracellular protein degradation. These emerging platforms could broaden the therapeutic applications of targeted protein degradation.

Targeted protein degradation has emerged as a powerful therapeutic strategy but remains limited by weak ternary complex formation, resistance mechanisms, and challenges associated with difficult-to-drug targets. This presentation will highlight our recent efforts to develop irreversible PROTACs and molecular glues that leverage transient or inducible interactions to achieve durable target engagement and enhanced degradation efficiency. We will discuss mechanistic insights, structural considerations, and emerging opportunities for expanding the degrader toolbox to overcome current limitations and unlock new therapeutic targets.

The talk will introduce a novel way of removing a protein from a cell i.e. by selectively blocking the translocation of nascent polypeptide chains using selective small molecule inhibitors of the Sec61 translocon.

Macrocycles are nature’s preferred choices to generate large cell-permeable bioactive molecules. They are also increasingly considered as modalities for difficult-to-bind proteins but strategies to best exploit their potential are only beginning to emerge. Our results highlight linkers as an opportunity for macrocyclic drug development, show how linker derivatization can improve the performance of macrocycles, and emphasizes the need to track macrocyclic scaffold evolution at a three-dimensional level.

Target degradation by PROTACs often exhibits a rebound kinetics where target protein is initially degraded followed by target rebound despite the continuous presence of PROTACs. We developed CG-SLENP technology to label new and old proteins in the same cells and we discovered that old proteins are more efficiently degraded while newly synthesized proteins are more resistant to degradation. This discovery adds a new dimension in PROTAC design and evaluation.