Next-Gen Degraders: Glues & Conjugates

The Rho family of small GTPases is crucial in multiple diseases, yet altering its function presents challenges due to its strong affinity for nucleotides and limited options for allosteric regulation. The GTPase Rac1 acts as a switch controlling cellular cytoskeletal activities and is implicated in numerous diseases. The RhoGEF Kalirin is a complex protein essential for synaptic and neuronal shape regulation in the brain, and disturbances in Kalirin function have been connected to several neurological conditions, including Alzheimer’s, schizophrenia, and bipolar disorder. We have developed covalent molecular glue fragments of Rac1/Kalirin which show selective inhibition for specific Rho GTPase/RhoGEF protein pairs.

Transcriptional regulation, the precise turning on and off of genes, is fundamental to cellular function. Equally integral to cellular life is the precise coming together of macromolecules to enable specific regulatory outcomes. Combining the two, we ask whether the targeted induction of proximity, mediated by heterobifunctional molecules, can rewire transcriptional programmes. This talk will highlight how Foghorn is exploring induced-proximity strategies to achieve both gene activation and repression.

Protein function and fate are governed by post-translational modifications (PTMs), most of which are catalysed by enzymes. Aberrant PTMs are a hallmark of many human diseases. Artificially inducing spatial proximity between a protein-modifying enzyme and a target protein in cells can enable precise rewriting of the PTM code, potentially offering a powerful way to rewire cell signalling. In this talk, I will cover the targeted degradation and dephosphorylation of several disease-causing proteins.

Stereoselective covalent ligands offer a powerful approach to define on-target activity in complex biological systems. We developed sulfonyl-triazole inhibitors of diacylglycerol kinases that induce paralog-selective membrane recruitment and suppress lipid signalling. Quantitative chemoproteomics identified key sites of modification, linking target engagement to proteasome-dependent degradation and enhanced T cell-mediated cytotoxicity against cancer cells. These findings position covalent targeting of lipid kinases as a promising strategy for immunotherapy.

Despite growing interest in PROTACs for neurodegenerative diseases, strategies to achieve BBB penetration and CNS activity remain unclear. We curated published PROTACs with demonstrated brain exposure and degradation, revealing key gaps: poor translation from rodent models, reliance on non-brain cell lines, and limited use of robust BBB assays. Current evidence suggests BBB-permeable PROTACs are not yet an established modality. We discuss emerging design trade-offs required to balance degradation efficiency with brain exposure, and present recent results from our laboratory that inform more realistic paths towards CNS-active PROTACs.

Proteolysis-targeting chimeras (PROTACs) require careful optimisation of properties such as molecular weight, polarity, lipophilicity, and flexibility to achieve oral bioavailability, aligning broadly with established bRo5 guidelines. While design principles for oral PROTACs are increasingly well understood, far less is known about requirements for inhaled delivery. This work highlights key parameters influencing pulmonary administration and presents two projects (HDAC6 and BET) aimed at developing inhaled PROTACs for respiratory diseases.

Rapafusyn Pharmaceuticals and Ternary Therapeutics will present the results of a collaboration for the AI-enabled design of non-degrading molecular glues for difficult-to-drug therapeutic targets. By combining Rapafusyn's rationally designed large DEL libraries with Ternary Therapeutics' Frontier AI models, we prospectively identified optimised molecular glues and design principles for the FKBP12-TRAF2 protein-protein interaction.

Targeting transcription factors remains a major therapeutic challenge due to their limited ligandable surfaces and complex regulatory functions. Here, we describe the development of a highly potent small-molecule degrader that selectively eliminates a disease-relevant transcription factor through the ubiquitin–proteasome system. The molecule also promotes higher-order polymeric assembly, revealing an unexpected mechanism for transcription factor degradation. 

Targeted protein degradation (TPD) is a potent strategy against intracellular proteins impervious to traditional drugs. We utilise platform-based screening and rational design to develop modular biological degraders. We demonstrate TPD efficacy against transcription factors across cancer models. Crucially, the distinct cellular responses observed between degradation and inhibition provide a powerful tool for enhancing our molecular understanding of protein function and offer new approaches for treating aggressive cancers.

STAT6 is the central transcription factor mediating IL-4/IL-13 signaling, a pathway critically implicated in atopic dermatitis and type II inflammatory diseases. In collaboration with Prof. Alessio Ciulli´s team at Dundee University, we converted Almirall's proprietary STAT6 binders into orally bioavailable VHL-based PROTACs with subnanomolar degradation potency. Functional effect across a range of primary cells was demonstrated, establishing a compelling path toward first-in-class oral therapy for type II inflammatory diseases.

Targeted degradation of age-related protein aggregates within cells is an exciting therapeutic approach. For the most common dementia, Alzheimer’s disease, the removal of tau aggregates is predicted to reverse cognitive decline. At TRIMTECH Therapeutics, we harness the innate properties of the ubiquitous E3 ligase TRIM21 to degrade disease-causing aggregates. Selective degradation of aggregated forms of proteins is achieved via a unique clustering activation mechanism (ligase-to-ligase proximity) that leaves the monomeric isoform of the target protein unaffected; demonstrating the potential of this next-generation TPD approach for the development of targeted therapies in proteinopathies.