Protein-Protein Interactions

My lab is working on the long-standing goal of developing cell membrane–permeable peptides for modulating intracellular targets and for oral delivery. We have developed nanoscale synthesis methods to generate and screen tens of thousands of sub-kDa synthetic peptides. My talk will highlight this platform and examples of successful ligand discovery, including membrane-permeable protein-protein inhibitors (unpublished) and orally available cyclic peptides.

The design of covalent drugs targeting residues other than Cys,  such as His, Lys, or Tyr, is gaining significant traction. I will discuss strategies and opportunities to design irreversible small molecule and constrained peptide-mimetic ligands that covalently target those residues. Both ligand-first,  structure-based design approaches, and covalent-fragment screening using aryl-fluorosulfate libraries will be presented with several examples.

Orally bioavailable cyclic peptides represent a promising class of therapeutic agents, offering significant potential to address unmet medical needs across various disease areas. This presentation highlights the discovery and preclinical development of novel orally active cyclic peptide inhibitors targeting PCSK9 for the treatment of hypercholesterolemia. We will present and discuss preclinical data on SG6001, a lead compound identified by Sungening, demonstrating its promise as an effective oral PCSK9 inhibitor.

Microcycles are head-to-tail cyclic hexapeptides that have proven effective against the most challenging targets. We present a HTS platform for the rapid intracellular generation and screening of a library of 3.2 million microcycles within disease-relevant mammalian cell lines. Examples will be presented that illustrate the inherent advantages of intracellular functional screens and scaffold hopping of hits into a small molecule backbone as a first step towards clinical candidates.

The substrate recognition site on Cyclins, endogenous cell cycle regulators that pair with and activate the CDKs, has been an attractive yet undruggable PPI target for decades. We report here our approach to optimisation of a novel, passively cell-permeable series of macrocyclic Cyclin A/B RxL inhibitors resulting in a lead compound with oral bioavailability across preclinical species and demonstrated anti-tumour activity in small-cell lung cancer models via oral dosing.

The discovery and optimisation of non-degrading molecular glues (MGs) represent a transformative approach in targeted protein modulation. Rapafusyn has pioneered the development of macrocyclic peptide molecular glues, leveraging innovative in-house developed machine learning (ML) and AI-driven strategies for prioritising target selection, proposing ternary complex structures and for scoring macrocyclic proposals for accessing topological diversity. Success stories from our recent DEL screening campaigns: TRAF2 (PPI target), TRADD (PPI target), STAT6 (transcription factor), and GSTP1 (enzyme target) will be presented. This presentation will provide an in-depth look at our innovative workflow, spanning from target selection to structural validation and drug-likeness optimisation.

THIS TALK HAS BEEN CANCELLED; WE ARE TRYING TO SPOTLIGHT SOME POSTERS INSTEAD IN THIS SLOT. THE SPEAKER WILL POST A RECORDING ON DEMAND FOR THOSE REGISTERED FOR THE MEETING. AND HE WILL SPEAK IN SAN DIEGO IN APRIL 2026.

Small-molecule stabilisation or induction of protein-protein interactions (PPIs) has become an attractive area in drug discovery. 14-3-3s are phospho-reader proteins with a huge interactome with many of its partner proteins being relevant for human disease, for example p53, ERalpha, Tau, aSyn, LRRK2, CFTR, and ChREBP. In this talk, the structural basis for 'glueing' 14-3-3/client interfaces is being discussed and how stabilisation of these 14-3-3 regulatory complexes result in therapeutically explorable target modulation. 

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP-TEAD complex is associated with diseases like cancer. Inhibition of YAP-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried P-site of TEAD is druggable. HDX experiments revealed how P-site binding compounds interfere with the formation of an active YAP-TEAD transcription complex. A cell-based screening approach delivered an azaindole hit that was optimised to in vivo active MSC-2723. Structure-derived scaffold modifications culminated in lactam-based MSC-9643, which demonstrated convincing synergism with an approved drug in vivo. Scaffold tuning provided brain penetrant inhibitor MSC-4070.

The success of sotorasib has revolutionised the treatment of Kirsten rat sarcoma (KRAS)-mutant non-small-cell lung cancer (NSCLC) with a codon 12 glycine-to-cysteine mutation (G12C). The discovery of structurally novel covalent KRAS G12C inhibitors remains a challenge, however, due in part to the moderate size of typical cysteine-reactive libraries. Here, we report the use of naïve DNA-encoded library (DEL) screening to identify a new KRAS inhibitor chemotype with promising biopharmaceutical properties. Utility of DEL technology and structure-based optimisation has been demonstrated by identification of a KRAS G12C inhibitor that afforded robust tumour-growth inhibition in a xenograft model.

Directly targeting the translation initiation factor eIF4F complex which includes eukaryotic initiation factors 4E (eIF4E), eIF4G, and eIF4A is a promising anticancer strategy. Astex applied NMR and x-ray crystallographic fragment screening to discover a novel binding site on eIF4E. Subsequent structure-guided design paired with targeted protein degradation and genetic rescue approaches, enabled the development and the functional characterisation of potent small molecule inhibitors of the eIF4E:eIF4G protein-protein interaction.

NRX-0305 is an orally bioavailable, pan-mutant BRAF degrader that targets Class 1/2/3 BRAF mutations while sparing wildtype BRAF. It potently degrades mutant BRAF, suppresses ERK signaling, and shows strong anti-tumor activity in vitro and in vivo, including BRAF inhibitorresistant and brain metastasis models. NRX-0305 also synergizes with MEK inhibition, offering a promising approach to overcome limitations of current BRAF inhibitors across diverse cancer settings.

Tumour Necrosis Factor Receptor 1 (TNFR1) plays a major role in immunoregulation. However, few small-molecule inhibitors of TNFR1 have been reported, despite potentially being good alternatives to existing antibody therapies. We report the discovery of a class of TNFR1 ligands using a fragment-based approach through NMR screening, followed by SPR and X-ray validation. From the hits, we have synthesised analogs with micromolar potency showing improved affinity towards TNFR1.