A5072599839- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Protein Degradation and Inhibitors
- CAR-T cell therapy research
- Synthesis and Biological Evaluation
- Real-Time Systems Scheduling
- Synthesis and Catalytic Reactions
- Oxidative Organic Chemistry Reactions
- Cancer, Hypoxia, and Metabolism
- Parallel Computing and Optimization Techniques
- Formal Methods in Verification
- Logic, programming, and type systems
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Embedded Systems Design Techniques
- Chemical Synthesis and Analysis
- Chemical Synthesis and Reactions
- Radiopharmaceutical Chemistry and Applications
- Phenothiazines and Benzothiazines Synthesis and Activities
- Genomics, phytochemicals, and oxidative stress
- Histone Deacetylase Inhibitors Research
- Radiology practices and education
- ATP Synthase and ATPases Research
- Synthesis and pharmacology of benzodiazepine derivatives
- Teaching and Learning Programming
Zhongshan Hospital
2024
Third Affiliated Hospital of Guangzhou Medical University
2023
Guangzhou Medical University
2023
Zhejiang University of Technology
2023
Sun Yat-sen University
2023
Jilin University
2023
WuXi AppTec (China)
2015-2022
China Medical University
2018
East China Normal University
2006
Abstract The ability to selectively degrade proteins with bifunctional small molecules has the potential fundamentally alter therapy in a variety of diseases. However, relatively large size these chimeric often results challenging physico‐chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their vivo applications. We recently discovered an exquisitely potent BET degrader (GNE‐987) exhibited picomolar cell potencies but also demonstrated...
Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform field medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) chemical literature, enable controlled degradation specific their direction cellular proteasome. In this report, we describe second phase our research focused on exploring antibody–drug conjugates (ADCs), which...
The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) related chimeric molecules that effect intracellular degradation target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these entities are relatively large compounds often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation such monoclonal antibodies using...
Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite progress, improvements ADC index are desired. Peptide-based linkers that cleaved lysosomal proteases shown sufficient stability serum effective payload-release targeted cells. If linker can be preferentially hydrolyzed tumor-specific proteases, safety margin may improve. However, use of peptide-based limits our ability to...
Disulfide bonds could be valuable linkers for a variety of therapeutic applications requiring tunable cleavage between two parts molecule (e.g., antibody–drug conjugates). The in vitro linker immolation β-mercaptoethyl-carbamate disulfides and DNA alkylation properties associated payloads were investigated to understand the determinant cell killing potency anti-CD22 linked pyrrolobenzodiazepine (PBD-dimer) conjugates. Efficient release PBD-dimer with strong observed following disulfide...
Conjugation of small molecule payloads to cysteine residues on proteins via a disulfide bond represents an attractive strategy generate redox-sensitive bioconjugates, which have value as potential diagnostic reagents or therapeutics. Advancement such “direct-disulfide” bioconjugates the clinic necessitates chemical methods form connections efficiently, without byproducts. The connection must also be resistant premature cleavage by thiols prior arrival at targeted tissue. We show here that...
Diverse biological roles for mitogen-activated protein kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function various disease contexts. In particular, compounds that can be used carry out such studies vivo would critical elucidating potential therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing ability cross into CNS led an advanced compound 13 (GNE-495) showed excellent...
Calicheamicin antibody-drug conjugates (ADCs) are effective therapeutics for leukemias with two recently approved in the United States: Mylotarg (gemtuzumab ozogamicin) targeting CD33 acute myeloid leukemia and Besponsa (inotuzumab CD22 lymphocytic leukemia. Both of these calicheamicin ADCs heterogeneous, aggregation-prone, have a shortened half-life due to instability acid-sensitive hydrazone linker circulation. We hypothesized that we could improve upon heterogeneity, aggregation,...
Endometriosis (EMS) is an estrogen-dependent disease. However, little known about the regulation of estrogen, a potential therapeutic target, in EMS, which remains very poorly managed clinic. We hypothesized that microRNAs (miRNAs) can be exploited therapeutically to regulate transcription factor 21 (TCF21) and steroidogenic factor-1 (SF-1) gene expression. In our study, paired eutopic ectopic endometrial samples were obtained from women with EMS processed by standard protocol obtain human...
The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism action (microtubule inhibition) and particular activity against multidrug-resistant tumor cells. Yet high potency subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in form antibody-drug conjugates (ADCs). Here we report a strategy prepare stable bioreversible antibodies without loss activity. A peptide trigger along with quaternary ammonium salt...
A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) in vitro the presence either glutathione (GSH) or cysteine (Cys). good correlation was observed between GSH stability and cytotoxicity toward tumor cell lines. The prodrug-containing compounds typically more potent against cells with relatively high intracellular levels (e.g., KPL-4 cells). Several antibody–drug...
Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody–drug conjugates (ADCs), and many examples currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer were modified by systematic introduction acidic basic moieties into their chemical structures. The impact these changes on DNA binding, cell membrane permeability, vitro antiproliferation potency was,...
Abstract A novel method for the synthesis of α‐chloroacetophenones using 1,3‐dichloro‐5,5‐dimethylhydantoin (DCDMH) and p‐toluenesulfonic acid in methanol at 30–35°C is described. Substituted acetophenones para position or meta aromatic ring give high yield. However, reaction o‐nitroacetophenone does not take place under same condition.
This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB (TDCs) containing entities shown to be highly efficacious in WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, seco-CBI-containing also observed undergo significant biotransformation vivo mice, rats, monkeys thereby form 1:1 adducts with Alpha-1-Microglobulin (A1M) plasma...
Abstract A novel strategy to attach indole‐containing payloads antibodies through a carbamate moiety and self‐immolating, disulfide‐based linker is described. This new was employed connect selective estrogen receptor down‐regulator (SERD) various in site‐selective manner. The resulting conjugates displayed potent, antigen‐dependent down‐regulation of levels MCF7‐neo/HER2 MCF7‐hB7H4 cells. They also exhibited similar modulation the tumors when administered intravenously mice bearing tumor...
A straightforward four-step synthesis of primary-amino-substituted naphthyridine esters from commercially available cyanopyridines was described. The route makes use a condensation reaction between pyridinyl acetates with <i>N</i>,<i>N</i>-dimethylformamide dimethylacetal (DMF-DMA) to form <i>ortho</i>-cyano vinylogous carbamates. These intermediates can undergo facile cyclization ammonium acetate in acetic acid generate the corresponding good synthetic yields. primary-amino-substituted...