Development of Potent and Selective CK1α Molecular Glue Degraders.

Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation.

Antitumor activity of selenopsammaplin A analog (SPA-10091-HCl) via histone methyltransferase DOT1L degradation and apoptosis induction in castration-resistant prostate cancer cells.

Castrate-resistant prostate cancer (CRPC) is one of the most difficult cancers in men and is characterized by a poor prognosis and a high risk of metastasis. The overexpression of the disruptor of telomeric silencing 1-like (DOT1L), which is a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), has been related to poor outcomes in patients with CRPC. Therefore, targeting DOT1L is considered a potential therapeutic approach to overcome the significant medical challenges of CRPC.

Malignant otitis externa: What is the role of surgery?

Objective: Malignant otitis externa (MOE) is typically managed with long-term broad-spectrum antibiotics. The impact of surgical intervention on clinical outcomes is not well described. This study aims to compare clinical outcomes of MOE patients managed with or without surgery.

Activating p53 with a Mutant-Specific Small Molecule.

is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 () due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription.

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging.

Anesthetic Management of Intracardiac Migration of Medical Devices.

The use of endovascular, percutaneous interventions to treat cardiac, arterial, and venous pathologies is becoming increasingly common in medical practice. While endovascular device placement typically carries a low risk, device migration remains a persistent problem with these procedures for which anesthesia providers must have a high index of suspicion. Anesthesia providers should be aware of the wide range of indications for such devices, potential migration locations, and hemodynamic consequences of both the inciting pathology and device migration so they can safely care for patients in these settings.

Discovery of electrophilic degraders that exploit SAr chemistry.

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles.

Exploration of the tunability of BRD4 degradation by DCAF16 trans-labelling covalent glues.

Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.

Beyond the bulk: overview and novel insights into the dynamics of muscle satellite cells during muscle regeneration.

Skeletal muscle possesses remarkable regenerative capabilities, fully recovering within a month following severe acute damage. Central to this process are muscle satellite cells (MuSCs), a resident population of somatic stem cells capable of self-renewal and differentiation. Despite the highly predictable course of muscle regeneration, evaluating this process has been challenging due to the heterogeneous nature of myogenic precursors and the limited insight provided by traditional markers with overlapping expression patterns.

Development of a molecular glue-based Lin28 degrader to regulate cellular proliferation and stemness.

Let-7 microRNAs (miRNAs) regulate cellular processes including stemness and proliferation. Lin28, an RNA-binding protein, controls let-7 miRNA biogenesis and is a key factor in maintaining stem cell properties. We developed SB1349, a novel molecular glue-based degrader targeting Lin28.

Evo312: An Evodiamine Analog and Novel PKCβI Inhibitor with Potent Antitumor Activity in Gemcitabine-Resistant Pancreatic Cancer.

As an obstinate cancer pancreatic cancer (PC) poses a major challenge due to limited treatment options which include resection surgery, radiation therapy, and gemcitabine-based chemotherapy. In cancer cells, protein kinase C βI (PKCβI) participates in diverse cellular processes, including cell proliferation, invasion, and apoptotic pathways. In the present study, we created a scaffold to develop PKCβI inhibitors using evodiamine-based synthetic molecules.

Template-assisted covalent modification underlies activity of covalent molecular glues.

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'.

Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7).

Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity.

Dynamic flow for efficient partial decellularization of tracheal grafts: A preliminary rabbit study.

Objective: Bioengineered tracheal grafts are a potential solution for the repair of long-segment tracheal defects. A recent advancement is partially decellularized tracheal grafts (PDTGs) which enable regeneration of host epithelium and retain viable donor chondrocytes for hypothesized benefits to mechanical properties. We propose a novel and tunable 3D-printed bioreactor for creating large animal PDTG that brings this technology closer to the bedside.

CO Enrichment Boosts Highly Selective Infrared-Light-Driven CO Conversion to CH by UiO-66/CoS Photocatalyst.

Photocatalytic CO reduction to high-value chemicals is an attractive approach to mitigate climate change, but it remains a great challenge to produce a specific product selectively by IR light. Hence, UiO-66/CoS composite is designed to couple the advantages of metallic photocatalysts and porous CO adsorbers for IR-light-driven CO-to-CH conversion. The metallic nature of CoS endows UiO-66/CoS with exceptional IR light absorption, while UiO-66 dramatically enhances its local CO concentration, revealed by finite-element method simulations.

Independent and joint associations of aerobic and muscle-strengthening exercise with mental health in adolescents: A cross-sectional analysis before and during COVID-19 using the 2015-2021 National Youth Risk Behavior Survey.

Purpose: COVID-19 led to social isolation that may have compromised adolescent mental health. This study examined the independent and joint associations of aerobic physical activity (PA) and muscle-strengthening exercise (MSE) with mental health problems in adolescents.

Methods: Participants were US adolescents who completed the 2015-2021 National Youth Risk Behavior Survey (N = 61,298; 45.

Exploration of the Tunability of BRD4 Degradation by DCAF16 -labelling Covalent Glues.

Small molecules that can induce protein degradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand the number of proteins that can be manipulated pharmacologically. Current strategies for targeted protein degradation are mostly limited in their target scope to proteins with preexisting ligands. Alternate modalities such as molecular glues, as exemplified by the glutarimide class of ligands for the CUL4 ligase, have been mostly discovered serendipitously.

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry.

Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation.

Partial decellularization eliminates immunogenicity in tracheal allografts.

There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long-segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea.

Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2).

Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10 e, a first-in-class small molecule degrader of PDCD2.