An industry perspective approach and control strategy for implementation of ready-to-use cells in bioassays: survey outcome and recommendations.

The BioPhorum Development Group is an industry collaboration enabling the sharing of common practices for the development of biopharmaceuticals. Bioassays are an important part of an analytical control system. Utilization of ready-to-use cells can increase operational flexibility and improve efficiency by providing frozen cell banks uniform stock while removing challenges associated with maintaining cultured cells.

Deep learning for de-convolution of Smad2 versus Smad3 binding sites.

Background: The transforming growth factor beta-1 (TGF β-1) cytokine exerts both pro-tumor and anti-tumor effects in carcinogenesis. An increasing body of literature suggests that TGF β-1 signaling outcome is partially dependent on the regulatory targets of downstream receptor-regulated Smad (R-Smad) proteins Smad2 and Smad3. However, the lack of Smad-specific antibodies for ChIP-seq hinders convenient identification of Smad-specific binding sites.

Designing a leucine-rich antibacterial nonapeptide with potent activity against mupirocin-resistant MRSA via a structure-activity relationship study.

Staphylococcus aureus is the main aetiological agent responsible for the majority of human skin infections. Of particular concern is the methicillin-resistant variety, commonly known as MRSA. The extensive use of the first-line topical antibiotic of choice, mupirocin, has inevitably resulted in the emergence of resistant strains, signalling an urgent need for the development of new antibacterials with new mechanisms of action.

Room-Temperature Patterning of Nanoscale MoS under an Electron Beam.

Molybdenum disulfide (MoS) is traditionally grown at a high temperature and subsequently patterned to study its electronic properties or make devices. This method imposes severe limitations on the shape and size of MoS crystals that can be patterned precisely at required positions. Here, we describe a method of direct nanoscale patterning of MoS at room temperature by exposing a molybdenum thiocubane single-source precursor to a beam of electrons.

Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2.

Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold.

Correction to "Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3".

[This corrects the article DOI: 10.1021/acsmedchemlett.9b00170.

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads.

Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.

The atypical protein kinase C-iota (PKC-ι) enzyme is implicated in various cancers and has been put forward as an attractive target for developing anticancer therapy. A high concentration biochemical screen identified pyridine fragment weakly inhibiting PKC-ι with IC = 424 μM. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-ι (IC= 270 nM).

Designing an ultra-short antibacterial peptide with potent activity against Mupirocin-resistant MRSA.

Staphylococcus aureus is the pathogen responsible for the majority of human skin infections. In particular, the methicillin-resistant variety, MRSA, has become a global clinical concern. The extensive use of mupirocin, the first-line topical antibacterial drug of choice, has led to the emergence of mupirocin-resistant MRSA globally, resulting in the urgent need for a replacement.

Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors.

Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.

Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis.

Structure-activity relationship studies of ultra-short peptides with potent activities against fluconazole-resistant Candida albicans.

Vulvovaginal candidiasis (VVC) is a genital fungal infection afflicting approximately 75% of women globally and is primarily caused by the yeast Candida albicans. The extensive use of fluconazole, the first-line antifungal drug of choice, has led to the emergence of fluconazole-resistant C. albicans, creating a global clinical concern.

Direct Patterning of Zinc Sulfide on a Sub-10 Nanometer Scale via Electron Beam Lithography.

Nanostructures of metal sulfides are conventionally prepared via chemical techniques and patterned using self-assembly. This poses a considerable amount of challenge when arbitrary shapes and sizes of nanostructures are desired to be placed at precise locations. Here, we describe an alternative approach of nanoscale patterning of zinc sulfide (ZnS) directly using a spin-coatable and electron beam sensitive zinc butylxanthate resist without the lift-off or etching step.

Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells.

Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2.

An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA).

The lack of new antibacterial drugs entering the market and their misuse have resulted in the emergence of drug-resistant bacteria, posing a major health crisis worldwide. In particular, meticillin-resistant Staphylococcus aureus (MRSA), a pathogen responsible for numerous human infections, has become endemic in hospitals worldwide. Drug repurposing, the finding of new therapeutic indications for approved drugs, is deemed a plausible solution to accelerate drug discovery and development in this area.

Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex.

The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models.

Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core.

A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g.

3-Deazaneplanocin A and neplanocin A analogues and their effects on apoptotic cell death.

3-Deazaneplanocin A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure-activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction.

Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor.

Recent biological and computational advances in drug design have led to renewed interest in targeted covalent inhibition as an efficient and practical approach for the development of new drugs. As part of our continuing efforts in the exploration of the therapeutic potential of resorcylic acid lactones (RALs), we report herein the design, synthesis, and biological evaluation of conveniently accessible RAL enamide analogues as novel covalent inhibitors of MAP kinase interacting kinases (MNKs). In this study, we have successfully demonstrated that the covalent binding ability of RAL enamides can be tuned by attaching an electron-withdrawing motif, such as an acyl group, to enhance its reactivity toward the cysteine residues at the MNK1/2 binding sites.

Elective gastrostomy, nutritional status and quality of life in advanced head and neck cancer patients receiving chemoradiotherapy.

Background: Chemoradiotherapy for treatment of advanced head and neck cancer (HNC) is used to achieve organ preservation without compromising survival. Because chemoradiotherapy usually impacts adversely on nutritional and functional status, feeding by percutaneous endoscopic gastrostomy (PEG) is often part of the management regimen for these patients, but the presence of a PEG tube can also be associated with reduced quality of life (QOL). This study aimed to examine the factors associated with PEG insertion and the effects of PEG use on QOL and functional outcomes in HNC patients receiving chemoradiotherapy.