A5100698419- Cytokine Signaling Pathways and Interactions
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Hepatocellular Carcinoma Treatment and Prognosis
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Liver Disease Diagnosis and Treatment
- Cancer Mechanisms and Therapy
- DNA Repair Mechanisms
- Quinazolinone synthesis and applications
- Cancer therapeutics and mechanisms
- Receptor Mechanisms and Signaling
- Biosensors and Analytical Detection
- Autophagy in Disease and Therapy
- Kruppel-like factors research
- Meningioma and schwannoma management
- PI3K/AKT/mTOR signaling in cancer
- Mycobacterium research and diagnosis
- Liver Disease and Transplantation
- Fibroblast Growth Factor Research
- Pancreatic function and diabetes
- Microgrid Control and Optimization
- PARP inhibition in cancer therapy
- Advanced Breast Cancer Therapies
Sichuan University
2016-2025
State Key Laboratory of Biotherapy
2016-2025
Air Force Medical University
2023-2025
Sun Yat-sen University
2024-2025
Tianjin Medical University General Hospital
2024
Shanghai Urban Construction Design and Research Institute (Group)
2023
West China Hospital of Sichuan University
2019-2023
Chinese Academy of Medical Sciences & Peking Union Medical College
2023
Guang’anmen Hospital
2023
China Academy of Chinese Medical Sciences
2023
The NLRP3 inflammasome is a multiprotein complex that component of the innate immune system, involved in production pro-inflammatory cytokines. Its abnormal activation associated with many inflammatory diseases. In this study, we designed and synthesized series inhibitors based on pyridazine scaffolds. Among them, P33 exhibited significant inhibitory effects against nigericin-induced IL-1β release THP-1 cells, BMDMs, PBMCs, IC50 values 2.7, 15.3, 2.9 nM, respectively. Mechanism studies...
ATM plays an important role in DNA damage response and is considered a potential target cancer therapies. In this study, goal-directed molecular generation approach based on ligand similarity specificity was applied to sample active molecules, they were screened virtually identify the theoretical lead compound 7a, which later shown inhibit adequately. However, there main concern about its poor metabolic stability vitro. Subsequent optimization performed improve potency selectivity toward...
Selective poly(ADP-ribose) polymerase 1 (PARP1) inhibitors not only exhibit antitumor efficacy but also offer the potential to mitigate toxicities typically associated with broader PARP inhibition. In this study, we designed and synthesized a series of small molecules targeting highly selective PARP1 inhibitors. Among these, T26 demonstrated excellent selectivity along capability effectively cross blood-brain barrier (BBB). exhibited an IC50 0.2 nM against PARP1, remarkable 610-fold over...
The application of drugs to regulate abnormal epigenetic changes has become an important means tumor treatment. In this study, we employed computer-aided design methods develop a novel deazapurine compound targeting DNA methyltransferase 1 (DNMT1). Through screening for enzyme activity, selectivity, and cellular efficacy, optimized three structural skeletons, ultimately yielding 55, exhibiting IC50 2.42 μM DNMT1. Compound 55 displayed excellent in vitro inhibitory effects on various...
A series of pyrrolo[2,3-d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory subnanomolar MV4-11 Molm-13 It also showed excellent in FLT3-ITD-D835V FLT3-ITD-F691L cells which resistant to quizartinib. Furthermore, exhibited over 40-fold selectivity toward relative c-Kit kinase, might reduce myelosuppression toxicity. Cellular assays demonstrated that inhibited...
Herein, we describe the design, synthesis, and structure–activity relationships of a series unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) FLT3 kinases. These screening cascades revealed 18e was preferred compound, with IC50 values 0.7 4 nM for JAK2 FLT3, respectively. Moreover, potent inhibitor 37-fold 56-fold selectivity over JAK1 JAK3, respectively, possessed an excellent profile other 100 representative In cytokine-stimulated...
Guided by molecular docking, a commonly used open-chain linker was cyclized into five-membered pyrrolidine to lock the overall conformation of propeller-shaped molecule. Different substituents were introduced moiety block oxidative metabolism. Surprisingly, it found that small methyl substituent could be alleviate metabolism while maintaining or enhancing potency, which described as "magic methyl". Further optimization around "3rd blade" propeller led identification series potent and...
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) has been demonstrated to be a promising target for treating inflammatory diseases. Herein, we describe the discovery and optimization of series RIPK2 inhibitors derived from an FLT3 inhibitor, CHMFL-FLT3-165. Compound 10w was identified possess IC50 value 0.6 nM greater than 50,000-fold selectivity over its family homologous RIPK1 (IC50 > 30 μM). It exhibited high inhibited prevent NOD-induced cytokine production following...
Huazhuo Tiaozhi granule (HTG) is a herbal medicine formula widely used in clinical practice for hypolipidaemic effects. However, the molecular mechanisms underlying dyslipidaemia treatment have not been well elucidated.A significant reduction levels of total cholesterol (TC) and low-density lipoprotein (LDL-C) was observed serum patients with after HTG treatment, without disruption aspartate transaminase (AST), alanine (ALT), urea nitrogen (BUN), creatinine (Cr). The rat model induced by...
Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with susceptibility DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in pursuit clinical potential for inhibitors as synergistic adjuncts chemo- or radiotherapy. Nevertheless, although substantial progress has discovery potent DNA-PK, trial landscape requires even more selective molecules. This necessitates further endeavors expand repertoire clinically...
Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce characterized by extensive cytoplasmic vacuolation in HeLa MDA-MB-231 cells. Notably, compound L22 exhibited remarkable interaction with PIKfyve kinase, boasting Kd value 0.47 nM, surpassing positive controls D-13 MOMIPP potency....
Deep generative models have become crucial tools in de novo drug design. In current for multiobjective optimization molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance diversity, we herein propose a local diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying constraints. Compared state-of-the-art methods, molecules generated by LSDC exhibit greater applied generation...
Haemophilus parasuis (H. parasuis) can invade the body and cause systemic infection under stress conditions. Marbofloxacin has been recommended for treatment of swine infections. However, few studies have investigated PK/PD characteristics cutoff (COPD) this drug against H. parasuis. MICs marbofloxacin 198 isolates were determined. The MIC50 MIC90 2 8 mg/L, respectively. An in vitro dynamic model was established to study relationship surrogate markers Cmax/MIC, Cmax/MPC (the maximum...
TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, structure–activity relationships (SARs) 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective inhibitors. Among them, compound 14l exhibited acceptable inhibition with an IC50 value 9 nM, showed satisfactory selectivity characteristics over other three homologous JAK kinases,...
In this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration the structure–activity relationship through introduction spirocyclic scaffolds based on reported TYK2 inhibitor 14l led to discovery superior derivative compound 48. Compound 48 showed excellent potency kinases with IC50 values 6 and 37 nM, respectively, exhibited more than 23-fold selectivity for JAK2. also demonstrated metabolic stability potent...
In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration the structure–activity relationship though cyclization modification based on previously reported compound 18e led to discovery superior derivative 13ac. Compound 13ac showed excellent potency kinase, SET-2, and Ba/F3V617F cells (high expression JAK2V617F mutation) with IC50 values 3, 11.7, 41 nM, respectively....