Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demon...

I spent years spouting conspiracy theories about vaccines. Now, as measles rages in my home of Alberta, I’m trying to convince vax-hesitant parents to inoculate their kids.

The effects of fluorine and chlorine on pharmaceutical systems are compared using a Molecular Matched Pair Analysis. Effects on binding constants, physicochemical properties such as lipophilicity and...

Proteolysis-targeting chimeras (PROTACs) are promising next-generation therapeutics for the degradation of disease-associated proteins. However, optimizing the physicochemical properties of PROTACs, p...

Chemical Inducers of Proximity DNA-Encoded Library (CIP-DEL) screening enables high-throughput discovery of compounds that induce protein–protein interactions, including Proteolysis-Targeting Chimeras...

HHS Secretary RFK Jr. sat down with Scripps News for a wide-ranging interview, discussing mRNA vaccine funding policy changes and a recent shooting at the Centers for Disease Control and Prevention.

Chemical inducers of proximity (CIPs) can elicit durable, and often neomorphic, biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This ...

GPR75 is one of the most promising emerging targets for the treatment of obesity and related co-morbidities, as its loss of function directly correlates with a decreased body mass index (BMI) in human...

The well documented difficulties associated with direct (hetero)arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxfor...

Molecular glues powerfully control protein proximity but have largely eluded direct screening. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for fun...

Moreno Ballesteros et al. introduce a site-resolved strategy combining genetic code expansion and bioorthogonal chemistry to evaluate how ligand binding sites influence targeted protein degradation. This approach offers a powerful framework to accelerate degrader design, enable target validation, and broadly explore the potential of induced proximity.

Androgen-independent prostate cancers, correlated with heightened aggressiveness and poor prognosis, are caused by mutations or deletions in the androgen receptor (AR) or the expression of truncated variants of AR that are constitutively activated. Currently, drugs and drug candidates against AR target the steroid-binding domain to antagonize or degrade AR. However, these compounds cannot therapeutically access largely intrinsically disordered truncated splice variants of AR, such as AR-V7, which only possess the N-terminal transactivation domain and DNA-binding domain and are missing the ligand-binding domain. Targeting intrinsically disordered regions within transcription factors has remained challenging and is considered “undruggable”. Herein, we leverage a cysteine-reactive covalent ligand library in a cellular screen to identify the degraders of AR and AR-V7 in androgen-independent prostate cancer cells. We identified a covalent compound, EN1441, that selectively degrades AR and AR-V7 in a proteasome-dependent manner through direct covalent targeting of intrinsically disordered cysteine C125 in the N-terminal transactivation domain of AR and AR-V7. EN1441 causes significant and selective destabilization of AR and AR-V7, leading to the aggregation of AR/AR-V7 and subsequent proteasome-mediated degradation. Consistent with targeting both AR and AR-V7, we find that EN1441 completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared with AR antagonists or degraders that only target the ligand-binding domain of full-length AR, such as enzalutamide and ARV-110. Our results put forth a pathfinder molecule EN1441 that targets an intrinsically disordered cysteine within AR to destabilize, degrade, and inhibit both AR and AR-V7 in androgen-independent prostate cancer cells and highlights the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets.

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

Development of targeted covalent inhibitors and covalent ligand-first approaches have emerged as a powerful strategy in drug design, with cysteines be…

Plasma protein binding is crucial for understanding pharmacokinetics, pharmacodynamics, and safety. However, it is often not considered to be a primary parameter for optimization in drug design. This study challenges that perspective by revisiting established pharmacokinetic models and analyzing rat pharmacokinetic data of 3357 compounds. Bidirectional strategies for clearance-dependent optimization of plasma protein binding have been elucidated to achieve suitable effective half-lives. The analysis demonstrates that strategically modulating plasma protein binding can enhance drug efficacy and safety, thereby supporting its role as a critical factor in drug design.