Design, Synthesis, and Biological Evaluation of 3,4-Dihydroisoquinolin-1()-one Derivatives as Protein Arginine Methyltransferase 5 Inhibitors for the Treatment of Non-Hodgkin's Lymphoma.

Through catalyzing the transfer of methyl groups onto the guanidinium of arginine, protein arginine methyltransferase 5 (PRMT5) was essential to the cell growth of cancer cells. By utilizing a scaffold hopping strategy, a novel series of 3,4-dihydroisoquinolin-1()-one derivatives were designed and synthesized. Through a systematic SAR study, demonstrated excellent PRMT5 inhibitory activity, potent antiproliferative activity against Z-138, favorable pharmacokinetic profiles, and low hERG toxicity.

Kinase-Bench: Comprehensive Benchmarking Tools and Guidance for Achieving Selectivity in Kinase Drug Discovery.

Developing selective kinase inhibitors remains a formidable challenge in drug discovery because of the highly conserved structural information on adenosine triphosphate (ATP) binding sites across the kinase family. Tailoring docking protocols to identify promising kinase inhibitor candidates for optimization has long been a substantial obstacle to drug discovery. Therefore, we introduced "Kinase-Bench," a pioneering benchmark suite designed for an advanced virtual screen, to improve the selectivity and efficacy of kinase inhibitors.

Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia.

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance.

Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis.

The retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of Th17 cells, associated with autoimmune diseases, making it a significant drug target. Herein, we designed and synthesized 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline derivatives, improving upon GSK2981278 to enhance bioavailability. Of which, exhibited superior bioavailability (F = 48.

Modulating JAK2/STAT3 signaling by quercetin in Qiling Baitouweng Tang: a potential therapeutic approach for diffuse large B-cell lymphoma.

Qiling Baitouweng Tang (QLBTWT) is a traditional clinical formula for treating diffuse large B-cell lymphoma (DLBCL), but its molecular action is not fully understood. This research is utilized in silico analysis and liquid chromatography tandem mass spectrometry (LC‒MS/MS) to identify the active constituents of QLBTWT with anti-DLBCL properties and their targets. The study identified 14 compounds, including quercetin, naringenin, and astilbin, as potentially effective against DLBCL.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor (), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models.

Natural products as potential lead compounds to develop new antiviral drugs over the past decade.

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances.

Challenges for the development of mutant isocitrate dehydrogenases 1 inhibitors to treat glioma.

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1).

Tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6.

Ethnopharmacological Relevance: Xanthium sibiricum Patrin ex Widder (X. sibiricum) are widely used traditional herbal medicines for arthritis treatment in China. Rheumatoid arthritis (RA) is characterized by progressive destructions of joints, which is accompanied by chronic, progressive inflammatory disorder.

Design and synthesis of selective FLT3 inhibitors via exploration of back pocket II.

The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. The authors used computational methods to systematically compare pocket similarity with 269 kinases.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC = 256 nM) and FLT3-ITD by 73 % and 25.

Medicinal Chemistry Strategies for the Development of Bruton's Tyrosine Kinase Inhibitors against Resistance.

Despite significant efficacy, one of the major limitations of small-molecule Bruton's tyrosine kinase (BTK) agents is the presence of clinically acquired resistance, which remains a major clinical challenge. This Perspective focuses on medicinal chemistry strategies for the development of BTK small-molecule inhibitors against resistance, including the structure-based design of BTK inhibitors targeting point mutations, e.g.

An efficient strategy for digging protein-protein interactions for rational drug design - A case study with HIF-1α/VHL.

The ubiquitination of the hypoxia-inducible factor-1α (HIF-1α) is mediated by interacting with the von Hippel-Lindau protein (VHL), and is associated with cancer, chronic anemia, and ischemia. VHL, an E3 ligase, has been reported to degrade HIF-1 for decades, however, there are few successful inhibitors currently. Poor understanding of the binding pocket and a lack of in-depth exploration of the interactions between two proteins are the main reasons.

Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction.

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice.

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia.

Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy.

Structural Analysis of Chemokine Receptor-Ligand Interactions.

This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure-activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor-ligand complexes that have not been crystallized.