In conjunction with the 8th TPD & Induced Proximity Summit

A major challenge in evaluating the suitability of ∼700 known and putative E3 ligases for target protein degradation (TPD) is the lack of ligase-specific binders. Here, we use genetic code expansion (...

Protein-protein interaction (PPI) networks play a central role in many biological processes and thus the possibility of modulating them using small molecules offers several biomedical and biotechnolog...

Proteolysis targeting chimera (PROTAC) technology has revolutionized targeted protein degradation via the ubiquitin–proteasome system. Despite their e…

Molecular glues are small drug-like molecules that induce de novo protein–protein interactions or facilitate pre-existing weak interactions between pr…

Targeted protein degradation (TPD) is a powerful strategy for targeting and eliminating disease-causing proteins. While heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) are more modular, th...

Targeted protein degradation (TPD) is an emerging pharmacological modality in cancer therapy. In this Review, Hinterndorfer et al. outline the mechanistic bases of TPD and discuss the characteristics,...

This review discusses the cellular pathways mediating Targeted Protein Degradation approaches and points to some gaps in our understanding of the biology of novel therapeutic tools such as PROTACs.

Here we describe ProtacID, a flexible BioID (proximity-dependent biotinylation)-based approach to identify PROTAC-proximal proteins in living cells. ProtacID analysis of VHL- and CRBN-recruiting PROTA...

Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and degradation of a target protein via recruitment to an E3 ligase. The linker influences many steps of ...

Development of VHL-recruiting PROTACs that degrade fall armyworm sfBRD3 and sfWDS proteins with high potencies in Sf9 cells and in full larvae, establishing the PROTAC modality as promising for agricu...

Technologies to modulate induced proximity at the cell surface advance the manipulation of diverse biological responses.

C-Terminal cyclic imides are posttranslational modifications on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modificati...

Toure et al. investigate a known challenge in CDK9 inhibition—the compensatory increase in MYC levels. They demonstrate that a selective CDK9 degrader with rapid kinetics circumvents this effect, prov...

Ubiquitin chains determine the fates of their modified proteins, including proteasomal degradation. Kiss et al. present UbiREAD, a technology to monitor cellular degradation and deubiquitination at hi...

ConspectusThe E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological d...

Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provi...

Deregulated transcription is a defining hallmark of cancer, especially pediatric malignancies, which are frequently driven by fusion transcription factors. Targeting transcription factors directly has...

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactiv...

IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or...

Abigail Brewer, a recently graduated PhD student, and Jin-Feng Zhao, a postdoctoral researcher, from Prof. Gopal Sapkota’s lab at the MRC Protein Phosphorylation and Ubiquitylation Unit have been awar...

Molecules that can perturb protein-protein interactions have an immense impact on chemical biology and therapeutics. However, such compounds typically rely on accessory proteins to function, such as E...

Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative d...

Celebrating and supporting the achievements of women in science, and all those who work to encourage girls and young women to engage with STEM subjects and stay in STEM careers around the world.

Nature - To mark International Women’s Day on 8 March, six award-winning female scientists highlight women who have inspired them by pushing innovative research and creating opportunities for others.

Efficiency metrics are useful in medicinal chemistry to track small molecule progress in lead optimization (LO). Molecular glue degraders are small molecules that mediate targeted protein degradation ...

Targeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degr…

Halda Therapeutics has started a clinical trial of its first-in-modality RIPTAC drug HLD-0915 in prostate cancer, to see if bifunctional drugs can provide tissue-specific activity.

While MYC is a significant oncogenic transcription factor driver of cancer, directly targeting MYC has remained challenging due to its intrinsic disorder and poorly defined structure, deeming it undru...

The undruggable drivers of head and neck tumors might be targeted indirectly through the kinase LZK.

The ubiquitin proteasome system (UPS) has been successfully hi-jacked by both bifunctional and monovalent small molecules to affect the degradation of proteins that were once considered undruggable. T...

Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors and degraders rely on the potentially genotoxic hydroxamate as a zinc-binding group (ZBG). In this study, we present the development of HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety as an alternative ZBG. This approach avoids the genotoxicity concerns of hydroxamates while maintaining potent HDAC6 degradation. We synthesized a series of CRBN- and VHL-recruiting PROTACs and identified several potent HDAC6 degraders (HDAC6 Dmax > 80%). Among these, 17c was the most effective, achieving an HDAC6 degradation of 91% and a DC50 value of 14 nM. Further characterization proved that 17c acts via the ubiquitin–proteasome system and chemoproteomics confirmed selective HDAC6 degradation over other HDAC isoforms.

Androgen-independent prostate cancers, correlated with heightened aggressiveness and poor prognosis, are caused by mutations or deletions in the androgen receptor (AR) or expression of truncated varia...

Targeted protein degradation (TPD) has garnered appreciable interest in drug discovery due to its unique mechanism of action - degradation of a target in an event-driven manner, instead of traditional...

Proteolysis-targeting chimeras (PROTACs©) have recently emerged as a promising new drug modality. Residing beyond the rule-of-five space, they pose challenges in terms of physicochemical properties. W...

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral admin...

We introduce GlueMap, a computational toolkit to discover and optimize molecular glues. GlueMap integrates structural and pharmacodynamic modeling, molecular dynamics (MD), and machine learning (ML) f...

The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability of degrader molecules to selectively modulate disease-relevant proteins. A key limitation to the broad application of TPD is its dependence on small-molecule ligands to target proteins of interest. This leaves unstructured proteins or those lacking defined cavities for small-molecule binding out of the scope of many TPD technologies. The use of proteins, peptides, and nucleic acids (otherwise known as “biologics”) as the protein-targeting moieties in degraders addresses this limitation. In the following sections, we provide a comprehensive and critical review of studies that have used proteins and peptides to mediate the degradation and hence the functional control of otherwise challenging disease-relevant protein targets. We describe existing platforms for protein/peptide-based ligand identification and the drug delivery systems that might be exploited for the delivery of biologic-based degraders. Throughout the Review, we underscore the successes, challenges, and opportunities of using protein-based degraders as chemical biology tools to spur discoveries, elucidate mechanisms, and act as a new therapeutic modality.

Ultra high-throughput chemistry carried out in 1536-well plates is increasingly utilized for reaction optimization protocols and direct-to-biology (D2B) platforms, where nanomolar quantities of the final product are directly assessed for biochemical or cellular activity without purification. As their popularity increases, it is crucial that the synthesis of these molecules is reliable and reproducible. Research in our laboratories has identified several nuances of amide couplings when performed on the nanoscale that result in poor translation from 1536-well plates to batch-scale reactions. This case study presents a nanoscale amide coupling reaction to synthesize 700 PROTAC molecules, which identified a range of factors crucial to reaction success on the nanoscale, despite having no influence on reaction conversion in batch. This work presents a guide for high-throughput chemists to consider when working in 1536-well plates and their importance in drawing conclusions from nanoscale synthesis.

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic degradation machinery. In proteasome-dependent TPD, exp...

The von Hippel-Lindau (VHL) E3 ubiquitin ligase has seen extensive research due to its involvement in the ubiquitin proteasome system and role as a tumor suppressor within the hypoxia signaling pat...

UM171 promotes corepressor degradation by acting as a molecular glue to induce KBTBD4–HDAC1/2 interactions with the help of inositol hexakisphosphate.