Oral estrogen receptor PROTAC® vepdegestrant (ARV-471) is highly efficacious as monotherapy and in combination with CDK4/6 or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.

PURPOSE: Estrogen Receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR or PI3K inhibitors is now a central strategy for the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC®) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition. RESULTS: Vepdegestrant induced ≥90% degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in-vitro and achieved significant tumor growth inhibition (TGI) (87-123%) in MCF7 orthotopic xenograft models, better than the ET agent fulvestrant (31-80% TGI). In the hormone-independent ER Y537S patient derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regressions and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the mTOR inhibitor everolimus, and the PI3K inhibitors alpelisib and inavolisib. CONCLUSIONS: Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

The Gaze Cueing Effect and Its Enhancement by Facial Expressions Are Impacted by Task Demands: Direct Comparison of Target Localization and Discrimination Tasks.

The gaze cueing effect is characterized by faster attentional orienting to a gazed-at than a non-gazed-at target. This effect is often enhanced when the gazing face bears an emotional expression, though this finding is modulated by a number of factors. Here, we tested whether the type of task performed might be one such modulating factor. Target localization and target discrimination tasks are the two most commonly used gaze cueing tasks, and they arguably differ in cognitive resources, which could impact how emotional expression and gaze cues are integrated to orient attention. In a within-subjects design, participants performed both target localization and discrimination gaze cueing tasks with neutral, happy, and fearful faces. The gaze cueing effect for neutral faces was greatly reduced in the discrimination task relative to the localization task, and the emotional enhancement of the gaze cueing effect was only present in the localization task and only when this task was performed first. These results suggest that cognitive resources are needed for gaze cueing and for the integration of emotional expressions and gaze cues. We propose that a shift toward local processing may be the mechanism by which the discrimination task interferes with the emotional modulation of gaze cueing. The results support the idea that gaze cueing can be greatly modulated by top-down influences and cognitive resources and thus taps into endogenous attention. Results are discussed within the context of the recently proposed EyeTune model of social attention.

Adapting and validating informatics competencies for senior nurse leaders in the Canadian context: Results of a Delphi study.

BACKGROUND: Nurse leaders in senior leadership positions in various parts of the world can play an important role in the acquisition, implementation and use of health information technologies. To date, international research related to nurse leader informatics competencies has been carried out in specific healthcare delivery contexts with very specific health information technology environments. In this body of literature, the definition of a 'nurse leader' has not been clearly defined. As a result, it is challenging for senior nurse leaders in leadership and management positions in other countries to apply this research to their unique contexts. PURPOSE: The objective of this study was to obtain consensus on the informatics competencies of priority to senior Canadian nurse leaders. The goal of completing this work was to adapt and validate a set of nurse leader informatics competencies to be endorsed and supported nationally. METHODS: This study used a modified Delphi technique with a panel of nurse leaders with significant informatics knowledge from across Canada. Three rounds of information gathering were completed electronically. In Round 1, participants were provided a series of 26 potential competency statements obtained from a review of the literature; they were asked to comment on the clarity and wording of each statement. Two statements were eliminated after Round 1 due to redundancy. In Rounds 2 and 3, participants rated the remaining competency statements on a 7-point Likert scale for relative priority to nurse leaders. RESULTS: A total of 25, 24 and 23 participants completed the survey in Rounds 1, 2 and 3 respectively. Consensus was achieved at the end of Round 3 with the inclusion of 24 competency statements. All of the statements had a mean of 5 or greater on a 7-point Likert scale (1=low priority and 7=high priority). CONCLUSIONS: The study participants agreed upon 24 informatics competency statements of priority to Canadian nurse leaders. These competencies will be presented to senior national nursing leaders and nursing informatics organizations for endorsement. Inspired by work completed in the United States, the authors plan to develop a self-assessment instrument for use by Canadian nurse leaders using the identified competency statements. Future anticipated work includes identifying and creating resources for nurse leaders to develop these important informatics competencies.

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure-Degradation Relationships.

The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1.

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities. Compound 3i is a potent hit (TBK1 DC50 = 12 nM, Dmax = 96%) with excellent selectivity against a related kinase IKKε, which was further used as a chemical tool to assess TBK1 as a target in mutant K-Ras cancer cells.

Function and structure of GFP-like proteins in the protein data bank.

The RCSB protein databank contains 266 crystal structures of green fluorescent proteins (GFP) and GFP-like proteins. This is the first systematic analysis of all the GFP-like structures in the pdb. We have used the pdb to examine the function of fluorescent proteins (FP) in nature, aspects of excited state proton transfer (ESPT) in FPs, deformation from planarity of the chromophore and chromophore maturation. The conclusions reached in this review are that (1) The lid residues are highly conserved, particularly those on the "top" of the ß-barrel. They are important to the function of GFP-like proteins, perhaps in protecting the chromophore or in ß-barrel formation. (2) The primary/ancestral function of GFP-like proteins may well be to aid in light induced electron transfer. (3) The structural prerequisites for light activated proton pumps exist in many structures and it's possible that like bioluminescence, proton pumps are secondary functions of GFP-like proteins. (4) In most GFP-like proteins the protein matrix exerts a significant strain on planar chromophores forcing most GFP-like proteins to adopt non-planar chromophores. These chromophoric deviations from planarity play an important role in determining the fluorescence quantum yield. (5) The chemospatial characteristics of the chromophore cavity determine the isomerization state of the chromophore. The cavities of highlighter proteins that can undergo cis/trans isomerization have chemospatial properties that are common to both cis and trans GFP-like proteins.

The Role of the Tight-Turn, Broken Hydrogen Bonding, Glu222 and Arg96 in the Post-translational Green Fluorescent Protein Chromophore Formation.

Green Fluorescent Proteins (GFP) and GFP-like proteins all undergo an autocatalytic post-translational modification to form a centrally located chromophore. Structural analyses of all the GFP and GFP-like proteins in the protein databank were undertaken to determine the role of the tight-turn, broken hydrogen bonding, Gly67, Glu222 and Arg96 in the biosynthesis of the imidazolone group from 65SYG67. The analysis was supplemented by computational generation of the conformation adopted by uncyclized wild-type GFP. The data analysis suggests that Arg96 interacts with the Tyr66 carbonyl, stabilizing the reduced enolate intermediate that is required for cyclization; the carboxylate of Glu 222 acts as a base facilitating, through a network of two waters, the abstraction of a hydrogen from the alpha-carbon of Tyr66; a tight-turn conformation is required for autocatalytic cyclization. This conformation is responsible for a partial reduction in the hydrogen bonding network around the chromophore-forming region of the immature protein.