An efficient C-glycoside production platform enabled by rationally tuning the chemoselectivity of glycosyltransferases.

Despite the broad potential applications of C-glycosides, facile synthetic methods remain scarce. Transforming glycosyltransferases with promiscuous or natural O-specific chemoselectivity to C-glycosyltransferases is challenging. Here, we employ rational directed evolution of the glycosyltransferase MiCGT to generate MiCGT-QDP and MiCGT-ATD mutants which either enhance C-glycosylation or switch to O-glycosylation, respectively.

Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies.

Background: Chronic Myeloid Leukemia (CML) is a blood cancer that remains challenging to cure due to drug resistance and side effects from current BCR-ABL inhibitors. There is an urgent need for novel and more effective BCR-ABL targeting inhibitors and therapeutic strategies to combat this deadly disease.

Method: We disclose an "OH-implant" strategy to improve a noncovalent BCR-ABL inhibitor, PPY-A, by adding a hydroxyl group to its scaffold.

Structure-Based Drug Design of 2-Amino-[1,1'-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of -Amplified Breast Cancer.

amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for amplification holds promise for the treatment of -amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design.

Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells.

Reversible lysine acetylation is an important post-translational modification (PTM). This process in cells is typically carried out enzymatically by lysine acetyltransferases and deacetylases. The catalytic lysine in the human kinome is highly conserved and ligandable.

Proteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles.

The evolving use of covalent ligands as chemical probes and therapeutic agents could greatly benefit from an expanded array of cysteine-reactive electrophiles for efficient and versatile proteome profiling. Herein, to expand the current repertoire of cysteine-reactive electrophiles, we developed a new class of strain-enabled electrophiles based on cyclopropanes. Proteome profiling has unveiled that C163 of lactate dehydrogenase A (LDHA) and C88 of adhesion regulating molecule 1 (ADRM1) are ligandable residues to modulate the protein functions.

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations.

Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge.

Kinase Inhibition via Small Molecule-Induced Intramolecular Protein Cross-Linking.

Remarkable progress has been made in the development of cysteine-targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e.

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors.

Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy.

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is a broad interest in the development of GPX4 inhibitors. However, a majority of reported GPX4 inhibitors utilize chloroacetamide as a reactive electrophilic warhead, and the selectivity and pharmacokinetic properties still need to be improved.

Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development.

Advances in targeted covalent inhibitors (TCIs) have been made by using lysine-reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell-active TCIs are however available. We report herein lysine-reactive activity-based probes (ABPs; 2-14) based on the chemistry of aryl fluorosulfates (ArOSO F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells.

5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression.

DNA methylation at the fifth position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification for regulating gene expression, but little is known about how it regulates gene expression in insects. Here, we pursue the detailed molecular mechanism by which DNMT1-mediated 5mC maintenance regulates female reproduction in the German cockroach, Blattella germanica. Our results show that Dnmt1 knockdown decreases the level of 5mC in the ovary, upregulating numerous genes during choriogenesis, especially the transcription factor ftz-f1.

Characteristics of fish community structure and environmental driving factors in Taihu Lake during the first year of fishing ban.

Taihu Lake has officially implemented the full fishing ban policy since October 1, 2020. We investigated fish community of Taihu Lake in the four seasons of 2020. A total of 42 fish species were collected, belonging to 6 orders, 7 families, and 33 genera.

Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors.

Right open reading frame kinase 2 (RIOK2) is an atypical kinase and has been proved to be involved in multiple human cancers including non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), glioblastoma and anemia. Although tremendous efforts have been devoted to the studies of RIOK2, its biological functions remain poorly understood. It is highly important to develop potent and selective RIOK2 inhibitors as potential research tools to elucidate its functions and as drug candidates for further therapies.

N-N-Bridged Polynuclear POM-Based Coordination Polymers Based on a V-Type Ligand: Proton Conduction and Magnetism.

The construction of polyoxometalate (POM)-based coordination polymers, in the presence of a nitrogen heterocyclic ligand, is intriguing due to the potential for obtaining diverse structures. These structures exhibit extensive application possibilities in the fields of proton conductivity and magnetism. Herein, four new POM-based polynuclear coordination polymers with the formulas of {[Fe(btb)(HO)(SiWO)]·3HO} (), {[Cd(btb)(HO)(HPMoMoO)]·2HO} (), {[Co(OH)(btb)(HO)(HPMoMoO)]·7HO} (), and {[Cu(OH)(btb)(HO)(HPMoO)]·6HO} () have been prepared using the V-type 1,3-bis(4-1,2,4-triazole-4-yl)benzene (btb) ligand.

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations.

Multitarget inhibitors/probes that target LRRK2 and AURORA A kinases noncovalently and covalently.

Herein, we report a salicylaldehyde-based, reversible covalent inhibitor (A2) that possesses moderate cellular activity against AURKA with a prolonged residence time and shows significant non-covalent inhibition towards LRRK2. Our results indicated that this multitarget kinase inhibitor may be used as the starting point for future development of more potent, selective and dual-targeting covalent kinase inhibitors against AURKA and LRRK2 for mitophagy.

Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles.

Owing to their remarkable pharmaceutical properties compared to those of noncovalent inhibitors, the development of targeted covalent inhibitors (TCIs) has emerged as a powerful method for cancer treatment. The K-Ras mutant, which is prevalent in multiple cancers, has been confirmed to be a crucial drug target in the treatment of various malignancies. However, although the K-Ras(G12D) mutation is present in up to 33% of K-Ras mutations, no covalent inhibitors targeting K-Ras(G12D) have been developed to date.

lncRNA ASBEL and lncRNA Erbb4-IR reduce chemoresistance against gemcitabine and cisplatin in stage IV lung squamous cell carcinoma via the microRNA-21/LZTFL1 axis.

Drug resistance is a major cause of treatment failure and post-treatment disease progression in patients with cancer. This study aimed to investigate the mechanisms of chemoresistance to gemcitabine (GEM) plus cisplatin (cis-diamminedichloroplatinum, DDP) combination therapy in stage IV lung squamous cell carcinoma (LSCC). It also examined the functional role of lncRNA ASBEL and lncRNA Erbb4-IR in the malignant progression of LSCC.

Ynamide Coupling Reagent for the Chemical Cross-Linking of Proteins in Live Cells.

Chemical cross-linking of proteins coupled with mass spectrometry analysis (CXMS) is a powerful method for the study of protein structure and protein-protein interactions (PPIs). However, the chemical probes used in the CXMS are limited to bidentate reactive warheads, and the available zero-length cross-linkers are restricted to 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/-hydroxysuccinimide (EDC/NHS) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). To alleviate this issue, an efficient coupling reagent, sulfonyl ynamide, was developed as a new zero-length cross-linker that can connect high-abundance carboxyl residues (D/E) with lysine (K) to form amide bonds in the absence of any catalyst.

Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD.

Hot Deformation Behavior and Processing Map Considering Strengthening Effect for Al-10.0Zn-3.0Mg-2.8Cu Alloy.

In this paper, a hot processing map that takes into the strengthening effect into account is optimized for the Al-10.0Zn-3.0Mg-2.