A5035978729- Ubiquitin and proteasome pathways
- Biochemical and Molecular Research
- Protein Degradation and Inhibitors
- Radical Photochemical Reactions
- Histone Deacetylase Inhibitors Research
- Synthesis and biological activity
- Cancer, Hypoxia, and Metabolism
- Quinazolinone synthesis and applications
- Chronic Lymphocytic Leukemia Research
- Kruppel-like factors research
- Cancer Mechanisms and Therapy
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cytokine Signaling Pathways and Interactions
- Protein Structure and Dynamics
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Catalytic C–H Functionalization Methods
- Multiple Myeloma Research and Treatments
- Chronic Myeloid Leukemia Treatments
- Asymmetric Hydrogenation and Catalysis
- Protein Kinase Regulation and GTPase Signaling
- Vascular Malformations and Hemangiomas
- PI3K/AKT/mTOR signaling in cancer
- Cancer Treatment and Pharmacology
- Vascular Tumors and Angiosarcomas
Mianyang Central Hospital
2023-2025
University of Electronic Science and Technology of China
2023-2025
Sichuan University
2014-2024
West China Hospital of Sichuan University
2020-2024
State Key Laboratory of Biotherapy
2021-2023
Chengdu University
2018-2021
Carboxylic acids are bench-stable and readily available chemical feedstocks that function as optimal fundamental synthetic platforms for the construction of C(sp3)–C(sp3) bonds via decarboxylation processes. We present a novel practical protocol decarboxylative alkylation Morita–Baylis–Hillman acetates with various carboxylic photoinduced iron-mediated ligand-to-metal charge transfer (LMCT) process under redox-neutral conditions. This method exhibits remarkable tolerance to wide array acids,...
Herein, a visible light-induced and metal-free strategy for the direct decarboxylative allylic alkylation of Morita–Baylis–Hillman acetates with aliphatic acids under redox-neutral conditions has been developed.
Lactate, a metabolic byproduct, has gained recognition as highly influential signaling molecule. Lactylation, an emerging form of post-translational modification derived from lactate, plays crucial role in numerous cellular processes such inflammation, embryonic development, tumor proliferation, and metabolism. However, the precise molecular mechanisms through which lactylation governs these biological functions both physiological pathological contexts remain elusive. Hence, it is imperative...
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...
Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, phase II clinical trial patients with bone-metastatic castration-resistant prostate cancer was halted because of lack efficacy. We previously reported KX01 binds to the colchicine site β-tubulin and its morpholine group lies close α-tubulin's surface. Thus, we hypothesized enhancing interaction α-tubulin could increase tubulin inhibition synthesized series...
So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting αβ-tubulin To further improve its antiproliferative activity, 66 derivatives or analogues 2 were designed and synthesized based on 2-tubulin cocrystal structure. Among them, 12b displayed nanomolar potency against variety tumor cells, including paclitaxel- adriamycin-resistant cell lines. binds the...
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...
Focal adhesion kinase (FAK) is a 125 kDa nonreceptor tyrosine that plays an important role in many carcinomas. Thus, the targeting of FAK by small molecules considered to be promising for cancer therapy. Some inhibitors have been reported as potential anticancer drugs and entered into clinical development; example, VS-4718 currently undergoing trials. However, lack crystal structural data binding with has hindered optimization this agent. In work, VS-4718/FAK interaction model was obtained...
Salt-inducible kinases (SIKs) are calcium/calmodulin-dependent protein kinase (CAMK)-like (CAMKL) family members implicated in insulin signal transduction, metabolic regulation, inflammatory response, and other processes. Here, we focused on SIK2, which is a target of the Food Drug Administration (FDA)-approved pan inhibitor N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (dasatinib), constructed four representative SIK2...
A novel and efficient method for the preparation of diarylmethyl sulfonamide derivatives has been achieved by visible-light-induced sulfamoylation para -quinone methides with sulfamoyl chlorides under mild metal-free conditions.
The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify functions. As more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as target protein. Molecular dynamics simulations binding free energy calculations were applied identify possible sites understand its recognition ability...
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...
Hydroxamic acid group is one of the characteristic pharmacophores histone deacetylase (HDAC) inhibitors. But here, we discovered a series hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening length linker in HDAC6 inhibitor SKLB-23bb. Interestingly, low nanomolar antiproliferative activity these MDAs depended on presence groups, but their inhibitory effects HDAC lost. Among them, 12b showed favorable metabolism stability, high bioavailability, and...
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...
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....
Abstract Janus kinase 2 (JAK2) hyperactivation by JAK2 V617F mutation leads to myeloproliferative neoplasms (MPNs) and targeting could serve as a promising therapeutic strategy for MPNs. Here, we report that Flonoltinib Maleate (FM), selective JAK2/FLT3 inhibitor, shows high selectivity over the JAK family. Surface plasmon resonance assays verified FM had stronger affinity pseudokinase domain JH2 than JH1 of an inhibitory effect on JH2V617F. The cocrystal structure confirmed stably bind JH2,...
The pH-dependent assembly of Toll-like receptors (TLRs), which triggers a threshold-like response, is key principle in immune signaling. While crystallography has revealed the intricate structure these complexes, mechanisms underlying their pH dependency remain unclear. Herein, constant simulations and metadynamics are employed to investigate stability TLR3/dsRNA signaling complex. findings demonstrate that system regulates complex by modulating protonation charge states histidines....
Skin radiation damage is a prevalent form of tissue injury encountered during radiotherapy, accidents, and occupational exposure. The only clinically approved radioprotective agent, amifostine, associated with numerous side effects, underscoring the urgent need for development safe effective agents. Natural products reductive properties possess high antioxidant activity biocompatibility, but their low bioavailability limits efficacy clinical application. To address this, we utilized...