A5101432732- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Chromatin Remodeling and Cancer
- Insect-Plant Interactions and Control
- Insect Pest Control Strategies
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- PARP inhibition in cancer therapy
- Sesquiterpenes and Asteraceae Studies
- Sirtuins and Resveratrol in Medicine
- Chemical Synthesis and Analysis
- Genomics and Chromatin Dynamics
- Phytochemistry and Biological Activities
- Computational Drug Discovery Methods
- Plant chemical constituents analysis
- Photodynamic Therapy Research Studies
- Calcium signaling and nucleotide metabolism
- Biological Activity of Diterpenoids and Biflavonoids
- Receptor Mechanisms and Signaling
- Acute Myeloid Leukemia Research
- RNA and protein synthesis mechanisms
- Adenosine and Purinergic Signaling
- Signaling Pathways in Disease
- Phenothiazines and Benzothiazines Synthesis and Activities
Novartis (United States)
2017-2025
Novartis (France)
2025
Cangzhou Normal University
2023
Shandong Academy of Agricultural Sciences
2023
Shihezi University
2023
Jiangsu Academy of Agricultural Sciences
2023
Novartis (Switzerland)
2022
China Pharmaceutical University
2021
State Key Laboratory of Natural Medicine
2021
Ministry of Agriculture and Rural Affairs
2020
Significance We describe the development of a small molecule that mediates degradation bromodomain and extra-terminal (BET) proteins its application in treatment castration-resistant prostate cancer (CRPC). Few therapeutic options exist to treat CRPC, especially CRPC tumors expressing constitutively active androgen receptor (AR) splice variants lack ligand-binding domain can effect androgen-independent transactivation target genes. Importantly, we demonstrate targeted BET using...
The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy the clinic. Conversion of a inhibitor (quizartinib) into proteolysis targeting chimera (PROTAC) results compound that induces degradation ITD mutant at low nanomolar concentrations. Furthermore, PROTAC capable inhibiting cell growth more potently than warhead alone while fewer off-target kinases. This enhanced antiproliferative activity...
Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in subset sarcomas and leukemias. Here, we used novel small molecule inhibitors degraders along with RNA interference to assess dependency on BRD9 context diverse hematological malignancies, including acute myeloid leukemia (AML), lymphoblastic (ALL), multiple myeloma (MM) model systems. Following depletion protein, AML cells...
WD repeat-containing protein 5 (WDR5) is essential for the stability and methyltransferase activity of mixed lineage leukemia 1 (MLL1) complex. Dysregulation
Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for treatment allergic inflammatory diseases, but to date, no inhibitor has been tested in patients. Herein, we disclose discovery preclinical profiling highly selective, oral GJG057 (compound 1), which...
Abstract Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments this nature have been limited fungal systems due lack mammalian genome-wide deletion collections. With example novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that CRISPR/Cas9 system enables generation transient homo- heterozygous libraries allows for...
Stem cells reside in a particular microenvironment known as niche. The interaction between extrinsic cues originating from the niche and intrinsic factors stem determines their identity activity. Maintenance of cell self-renewal are to be controlled by chromatin factors. Herein, we use Drosophila adult testis which has two lineages, germline (GSC) lineage cyst (CySC) lineage, study how regulate differentiation. We find that factor Enhancer Polycomb [E(Pc)] acts CySC negatively control...
The effects of the flavonoid rutin on anticoagulant activity oral warfarin and protein binding pharmacokinetics its enantiomers were investigated in rats.A single dose racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or day 5 an 8-day regimen rutin, 1 g/kg daily.Rutin reduced effect evident as a 31% reduction area under prothrombin complex activty-time curve (P < 0.05).Rutin had no apparent pre-treatment baseline blood coagulation. It enhanced in-vitro serum S-...
Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas potent inhibiting motif. We explored SAR series, including 5 6 amino pyridines, using convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent vitro potency good ADME properties culminated compound 27.
Focal cortical dysplasias (FCDs) are major brain malformations that commonly lead to medically intractable epilepsy. The purinergic ionotropic P2X7 receptor (P2X7R) is an atypical P2X subtype gates calcium and sodium ions. Previous animal studies have suggested P2X7R a contributing factor in epileptogenesis. This study aimed define the distribution expression of 35 FCD patient-surgical-resection specimens relative autopsy control samples (n = 8). Immunohistochemical colocalization assays...
Osthole, the dominant bioactive constituent in Cnidium monnieri, has shown acute pesticidal activities. However, its detailed toxicity, antifeedant, and oviposition preference effects against agricultural pests have not been fully understood, limiting practical use. This study aimed to investigate contact antifeedant activity, of osthole three (Tetranychus urticae, Myzus persicae, Bactrocera dorsalis). Our results showed that monnieri (L.) Cusson (CMC) a high content 11.4 mg/g. Osthole...
Bromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting structure and composition associated members. To enable study ligand engaged assemblies, we established chemoproteomics approach using functionalized derivative BI-9564 as an affinity matrix. Unexpectedly,...
While adding the structural features that are more favored by on-target activity is common strategy in selectivity optimization, opposite of subtracting contribute to off-target can also be very effective. Reported here our successful effort improving kinase type II maternal embryonic leucine zipper inhibitors applying these two complementary approaches together, which clearly demonstrates powerful synergy between them.
Diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor Pradigastat (1) was shown to be effective at decreasing postprandial triglyceride levels in a patient population with familial chylomicronemia syndrome (FCS). Although pradigastat does not cause photosensitization humans the high clinical dose of 40 mg, positive signal observed preclinical models phototoxicity. Herein, we describe phototoxicity mitigation strategy for diarylamine containing molecules utilizing introduction an amide or...
Background: Fibroblast growth factor 21 (FGF21), an FGF family member, is atypical hormone and pro-longevity factor.Methods: To better understand of the effects exogenous administration FGF21 on lifespan stress tolerance, underlying molecular basis, we used silkworm, Bombyx mori, as experimental animal model to evaluate FGF21's pharmaceutical effects.Results: Lifespan was significantly prolonged in female silkworms with replenishment, whereas no effect observed male silkworms.FGF21...
BI-167107 is a new long-acting β 2 -adrenergic receptor (β -AR) agonist, and has important application in determining the critical structures of receptor/ligand proteins complex G-protein-coupled (GPCR).By employing 2-nitroresorcinol as starting material, practical synthetic route for been developed, involving 7-step reactions.The structure target molecule confirmed by 1 H NMR, 13 C NMR MS techniques.The advantages include avoiding use toxic reagents being suitable scale up preparation other...
A new sesquiterpenoid, namely vernocinolide A, as well ten known ones, were isolated from the ethyl acetate soluble fraction of Vernoniacinerea. The structure was elucidated by spectroscopic methods. Among sesquiterpenoids, nine them this plant for first time.
Effenburger 环化等一系列步骤得到关键桥环中间体(±)-1-羟基-5,5-二甲基-4,6-双(3-甲基-丁
Correction to: Sesquiterpene Lactones with Potent Cytotoxic Activities from Vernonia chinensisPlanta Med 2005; 71(10): 949-954DOI: 10.1055/s-2005-871212