CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells.

High mortality and low response rates in lung cancer patients call for novel therapeutic targets. Data mining of whole-genome genetic dependency screens suggest Cell Division Cycle 40 (CDC40) to be an essential protein for lung cancer cell survival. We characterized CDC40 knockdown effects in multiple lung cancer cell lines, revealing induced cell cycle defects that resulted in strong growth inhibition and activation of apoptosis.

Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity.

Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs.

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats.

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.

ChemoDOTS: a web server to design chemistry-driven focused libraries.

In drug discovery, the successful optimization of an initial hit compound into a lead molecule requires multiple cycles of chemical modification. Consequently, there is a need to efficiently generate synthesizable chemical libraries to navigate the chemical space surrounding the primary hit. To address this need, we introduce ChemoDOTS, an easy-to-use web server for hit-to-lead chemical optimization freely available at https://chemodots.

Discovery of Conformationally Constrained ALK2 Inhibitors.

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of , a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2.

Barriers, perceived benefits and preferences to exercise in adults with an opioid use disorder in the U.S.

Introduction: Over 10 million Americans misuse opioids and more than 5 million have been diagnosed with an opioid use disorder (OUD). In 2021, over 100,000 Americans died of a drug overdose and more than 75% of these deaths involved an opioid. Exercise has been shown to increase abstinence and decrease anxiety and depression in people with a substance use disorder.

From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia.

Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning.

Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein-Protein Interaction: A Semi-Automated "Hit Identification-to-Optimization" Approach.

The rapid identification of early hits by fragment-based approaches and subsequent hit-to-lead optimization represents a challenge for drug discovery. To address this challenge, we created a strategy called "DOTS" that combines molecular dynamic simulations, computer-based library design (chemoDOTS) with encoded medicinal chemistry reactions, constrained docking, and automated compound evaluation. To validate its utility, we applied our DOTS strategy to the challenging target syntenin, a PDZ domain containing protein and oncology target.

"I don't go to funerals anymore": how people who use opioids grieve drug-related death in the US overdose epidemic.

Background: Opioid-related overdose death is a public health epidemic in much of the USA, yet little is known about how people who use opioids (PWUO) experience overdose deaths in their social networks. We explore these experiences through a qualitative study of opioid-related overdose death bereavement among PWUO.

Methods: We recruited 30 adults who inject opioids from a syringe service program in the Midwestern USA and interviewed them using a semi-structured guide that addressed experiences of opioid use, opioid-related overdose, and overdose reversal via the medication naloxone.

Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the β-catenin protein.

CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation.

Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (BET) BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII-selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds.

Harshness and unpredictability: Childhood environmental links with immune and asthma outcomes.

The environment has pervasive impacts on human development, and two key environmental conditions - harshness and unpredictability - are proposed to be instrumental in tuning development. This study examined (1) how harsh and unpredictable environments related to immune and clinical outcomes in the context of childhood asthma, and (2) whether there were independent associations of harshness and unpredictability with these outcomes. Participants were 290 youth physician-diagnosed with asthma.

Disproportionate School Punishment and Significant Life Outcomes: A Prospective Analysis of Black Youths.

This study tested relationships between racial inequalities in the school system-specifically, the disproportionate punishment of Black students-and life outcomes for Black youths, along with moderating psychological factors. In an 18-year longitudinal study of 261 Black youths (ages 11-29), we investigated whether adult life outcomes varied as a function of adolescent self-control and academic achievement. We tested whether relationships were moderated by the racial climates of the high schools that youths attended, using administrative data on relative punishment rates of Black and White students.

Effects of social support in an academic context on low-grade inflammation in high school students.

Bolstering academic motivation is a high priority in school settings, but some evidence suggests this could take a toll on students' physical health. To address this, this study compared the effects of an experimental manipulation of academic motivation alone (AM) to academic motivation enhanced with social support (SS + AM) on markers of inflammation in a sample of 80 high school 9th graders. Outcomes included low-grade inflammation: C-reactive protein (CRP) and interleukin-6 (IL-6); a motivation measure; and grade point average (GPA), taken at baseline and follow-up (beginning and end of school year, respectively).

Gender Differences in Psychosocial Outcomes of Hair Loss Resulting from Childhood Irradiation for Tinea Capitis.

Recent studies have linked hair loss due to childhood irradiation for tinea capitis, a fungal infection of the scalp, to adverse psychosocial and health outcomes in women. However, no study to date has examined gender differences in the outcomes of this type of hair loss. The current study aimed to investigate gender differences in health and psychosocial outcomes of hair loss resulting from childhood irradiation for tinea capitis, and to identify the risk factors associated with depression in both men and women.

Fragment-based drug design targeting syntenin PDZ2 domain involved in exosomal release and tumour spread.

Syntenin stimulates exosome production and its expression is upregulated in many cancers and implicated in the spread of metastatic tumor. These effects are supported by syntenin PDZ domains interacting with syndecans. We therefore aimed to develop, through a fragment-based drug design approach, novel inhibitors targeting syntenin-syndecan interactions.

Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains.

PDZ domains, which belong to protein-protein interaction networks, are critical for regulating important biological processes such as scaffolding, trafficking, and signaling cascades. Interfering with PDZ-mediated interactions could affect these numerous biological processes. Thus, PDZ domains have emerged as promising targets to decipher biological phenomena and potentially treat cancer and neurological diseases.

Resting-State Functional Connectivity of the Central Executive Network Moderates the Relationship Between Neighborhood Violence and Proinflammatory Phenotype in Children.

Background: Neighborhood violence increases children's risk for a variety of health problems. Yet, little is known about biological pathways involved or neural mechanisms that might render children more or less vulnerable. Here, we address these questions by considering whether neighborhood violence is associated with the expression of a proinflammatory phenotype and whether this relationship is moderated by resting-state functional connectivity (rsFC) of the central executive network (CEN).

Pharmacological inhibition of syntenin PDZ2 domain impairs breast cancer cell activities and exosome loading with syndecan and EpCAM cargo.

Exosomes support cell-to-cell communication in physiology and disease, including cancer. We currently lack tools, such as small chemicals, capable of modifying exosome composition and activity in a specific manner. Building on our previous understanding of how syntenin, and its PDZ partner syndecan (SDC), impact on exosome composition we optimized a small chemical compound targeting the PDZ2 domain of syntenin.

Correction to: Hair loss due to scalp ringworm irradiation in childhood: health and psychosocial risks for women.

An amendment to this paper has been published and can be accessed via the original article.

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor.

The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors.

Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives.

The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against , and Gram-positive bacteria, including naïve or resistant , and with minimal inhibitory concentration (MIC) of 3.

Hair loss due to scalp ringworm irradiation in childhood: health and psychosocial risks for women.

Background: Until 1960, hundreds of thousands of children worldwide had been treated for scalp ringworm by epilation via irradiation. The discovery of late health effects in adulthood prompted investigation of the medical aspects of irradiation in childhood and led to the establishment of strict protocols for the use of X-ray irradiation. These studies ignored alopecia, which affects some individuals who underwent irradiation for scalp ringworm as children.