Scientific Reports - Orthogonal validation of PROTAC mediated degradation of the integral membrane proteins EGFR and c-MET

Comprehensive review presenting the different drug discovery approaches that until now have been employed in academic and pharmaceutical settings to identify new E3 ligase small molecules ligands and...

It has been shown that targeting receptor-interacting protein kinase 1 (RIPK1) can improve response to immune checkpoint inhibitors. Here, using PROTAC technology, the authors report the design and ch...

Recent drug discovery breakthroughs led to the approval of KRASG12C inhibitors in lung adenocarcinoma (LUAD). Unfortunately, clinical responses remain limited due to rapid resistance onset. Proteolysi...

Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genet...

Modular synthetic G-protein-coupled receptors with nanobody-based ligand-recognition domains can be designed and used to programme transgene expression, real-time fluorescence or endogenous G-protein ...

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but e...

The oxidative stress response is centered on the transcription factor NRF2 and protects cells from reactive oxygen species (ROS). While ROS inhibit the E3 ligase CUL3-KEAP1 to stabilize NRF2 and elici...

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but e...

The drug development landscape is expanding to include drug modalities such as PROteolysis-TArgeting Chimeras (PROTACs) and peptides, offering possibilities for previously intractable biological targets. However, with their size and chemical nature, they diverge from established frameworks for the prediction of oral bioavailability. This evolution to larger and more complex molecules necessitates new methodologies and prediction models to continuously expand on bioavailability guidelines. We describe the high-capacity adoption of two chromatographic physicochemical assays and their application for iterative compound optimization to achieve oral bioavailability. We further describe how these data underpin the continuous refinement of internal machine learning models, which guide compound synthesis decisions in the molecular design phase. Based on data for a set of 691 PROTACs, and two project examples, we confirm a sweet spot for oral bioavailability at log D values higher than the norm for small molecules and show how experimental data and prediction models synergize to effectively drive chemistry optimization.

TEAD proteins are the main transcriptional effectors of the Hippo signaling pathway and a pharmacological target in oncology. Most TEAD-targeting small molecules act by disrupting interaction with the...

The authors show that DCAF1, a substrate receptor of CUL4 and EDVP E3 ligases, can be recruited by PROTACs to degrade the cancer drug target, WDR5. They also report the crystal structures of PROTAC te...