A5024885870- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- HIV/AIDS drug development and treatment
- Estrogen and related hormone effects
- Prostate Cancer Treatment and Research
- Cancer-related gene regulation
- Ferroptosis and cancer prognosis
- Click Chemistry and Applications
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
- Free Radicals and Antioxidants
- Neuroscience and Neuropharmacology Research
- Cholesterol and Lipid Metabolism
- Neurological Disease Mechanisms and Treatments
- RNA modifications and cancer
- Growth Hormone and Insulin-like Growth Factors
- Glycosylation and Glycoproteins Research
- NF-κB Signaling Pathways
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Hormonal Regulation and Hypertension
- Biochemical effects in animals
- Cancer, Lipids, and Metabolism
Ningbo No. 2 Hospital
2023-2025
Guangzhou Institutes of Biomedicine and Health
2016-2024
University of Chinese Academy of Sciences
2016-2023
Guangzhou Medical University
2018-2022
Chinese Academy of Sciences
2016-2022
Guangzhou Regenerative Medicine and Health Guangdong Laboratory
2019
The transcriptional coactivator cAMP response element binding protein (CREB)-binding (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such acute myeloid leukemia (AML). Herein, we report the design, synthesis, biological evaluation of a series cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on inhibitor CCS1477. representative compounds
The discovery of inhibitors bromodomain and extra terminal domain (BET) has achieved great progress, at least seven have progressed into clinical trials for the treatment cancer or inflammatory diseases. Here, we describe identification, optimization, evaluation benzo[cd]indol-2(1H)-one containing compounds as a new class BET inhibitors, starting from structure-based virtual screening (SBVS). Through potent were obtained with significantly improved activity. two most bind to BRD4...
A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One the representative compounds, 7f, bound with DDR1 a Kd value 5.9 nM suppressed kinase activity an half-maximal (50%) inhibitory concentration 14.9 nM. 7f potently inhibited collagen-induced signaling epithelial–mesenchymal transition, dose-dependently colony formation pancreatic cancer cells, exhibited promising in vivo therapeutic...
The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, evaluation benzo[d]isoxazole-containing compounds potent BET inhibitors. Cocrystal structures representative inhibitors in complex with BRD4(1) provided solid structural basis compound optimization. two most compounds, 6i (Y06036) 7m (Y06137), bound to Kd values 82 81 nM,...
CREB (cyclic-AMP responsive element binding protein) protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of series 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led compound 9g (Y08284), which possesses good liver microsomal stability pharmacokinetic properties (F = 25.9%). Furthermore, able inhibit well proliferation,...
Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, biological evaluation endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with aim inducing in cells. Our efforts led to discovery compound
The death signaling complex comprising extrasynaptic NMDAR and TRPM4 plays a pivotal role in the pathogenesis of ischemic stroke. Targeting protein-protein interactions between represents promising therapeutic strategy for Herein, we describe discovery novel series NMDAR/TRPM4 interaction interface inhibitors aimed at enhancing neuroprotective efficacy optimizing pharmacokinetic profiles. representative compound
Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary consider the potential off-target toxicity associated with inhibition of four BET BD2 proteins. To date, no BRD4 domain selective inhibitor has reported. Based on our previous pan-BD2
Discoidin-domain receptors 1 and 2 (DDR1 DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed optimized to coinhibit DDR1 DDR2. One the most promising compounds, 5n, tightly bound DDR2 proteins with Kd values 7.9 8.0 nM; potently inhibited kinases IC50 9.4 20.4 nM, respectively; was significantly less potent a panel 403 wild-type at 1.0 μM. DDR1- DDR2-kinase inhibition by 5n validated Western-blotting analysis in primary...
The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) TRβ mutants remain challenging tasks. In this study, we first adopted the strategy breaking "His-Phe switch" to solve two problems, simultaneously. A structure-based approach was successfully utilized obtain compound 16g, which is a potent agonist (EC50: 21.0 nM, 85.0% maximum efficacy 1) with outstanding selectivity for over TRα also effectively activates TRβH435R mutant. Then, developed highly...
Prostate cancer is a commonly diagnosed and leading cause of cancer-related deaths. The bromodomain extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment castration-resistant prostate cancer. A series 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed synthesized selective containing protein 4 (BRD4) inhibitors. compounds potently inhibit BRD4(1) with nanomolar IC50 values exhibit high selectivity over most non-BET...
Receptor-related orphan receptor γ (RORγ) has emerged as an attractive therapeutic target for the treatment of cancer and inflammatory diseases. Herein, we report our effort on discovery, optimization, evaluation benzothiazole benzimidazole derivatives novel inverse agonists RORγ. The representative compound 27h (designated XY123) potently inhibited RORγ transcription activity with a half-maximal inhibitory concentration (IC50) value 64 nM showed excellent selectivity against other nuclear...
Abstract XY153 is a promising BET BD2 inhibitor with an IC 50 value of 0.79 nM against BRD4 BD2. It shows 354‐fold selectivity over BRD4‐BD1 and 6‐fold other domains. However, the reported synthesis route its derivatives are extremely poor‐yielding. After three key fragments, can only be obtained yield 1.3 % in original four‐step reaction. In this study, we three‐step alternative process XY153. The reaction conditions for were thoroughly investigated optimized, resulting significantly...
The epigenetic target CREB (cyclic-AMP responsive element binding protein) protein (CBP) and its homologue p300 were promising therapeutic targets for the treatment of acute myeloid leukemia (AML). Herein, we report design, synthesis, evaluation a class CBP/p300 PROTAC degraders based on our previously reported highly potent selective inhibitor