A5101398996- Cancer therapeutics and mechanisms
- Fluorine in Organic Chemistry
- Synthesis and Biological Evaluation
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Protein Tyrosine Phosphatases
- Biochemical and Molecular Research
- Cancer Mechanisms and Therapy
- Synthesis and Reactions of Organic Compounds
- Click Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- Cytokine Signaling Pathways and Interactions
- Fibroblast Growth Factor Research
- Chronic Lymphocytic Leukemia Research
- Drug Transport and Resistance Mechanisms
- Peptidase Inhibition and Analysis
- Lung Cancer Treatments and Mutations
- Antibiotic Resistance in Bacteria
- Cancer, Hypoxia, and Metabolism
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Bioactive Compounds and Antitumor Agents
- Computational Drug Discovery Methods
Shandong University of Traditional Chinese Medicine
2024
Affiliated Hospital of Shandong University of Traditional Chinese Medicine
2024
Roche (China)
2018-2021
The application of artificial intelligence (AI) has been considered a revolutionary change in drug discovery and development. In 2020, the AlphaFold computer program predicted protein structures for whole human genome, which remarkable breakthrough both AI applications structural biology. Despite varying confidence levels, these could still significantly contribute to structure-based design novel targets, especially ones with no or limited information. this work, we successfully applied our...
Cyclin-dependent kinases 12 and 13 (CDK12/13) safeguard genomic integrity by preferentially regulating gene expression in the DNA damage response (DDR). The CDK12/13-mediated upregulation of DDR genes pathways significantly contributes to both tumorigenesis development resistance antitumor therapies. Thus, functional inhibition CDK12/13 offers an attractive strategy combat carcinogenesis, particularly for refractory treatment-resistant cancers. Here, we report discovery compound 12b as a...
The rise of multidrug resistant (MDR) Gram-negative (GN) pathogens and the decline available antibiotics that can effectively treat these severe infections are a major threat to modern medicine. Developing novel against MDR GN is particularly difficult as compounds have permeate double membrane, which has very different physicochemical properties, circumvent plethora resistance mechanisms such multiple efflux pumps target modifications. bacterial type II topoisomerases DNA gyrase (GyrA2B2)...
Cyclin-dependent kinase 8 (CDK8), as a subunit of the Mediator complex, is involved in regulation RNA polymerase II-mediated transcription, thereby modulating multiple signaling pathways and transcription factors oncogenic control. CDK8 deregulation has been implicated human diseases, particularly acute myeloid leukemia (AML) advanced solid tumors, where it reported putative oncogene. Here, we report successful optimization an azaindole series inhibitors that were identified further...
Stabilization of hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase domain enzymes (PHDs) represents a breakthrough in treating anemia associated with chronic kidney disease. Here, we identified novel scaffold for noncarboxylic PHD inhibitors utilizing structure-based drug design (SBDD) and generative models. Iterative optimization potency solubility resulted compound 15 which potently inhibits thus stabilizing HIF-α vitro. X-ray cocrystal structure confirmed the binding model...
The mediator kinases CDK8 and CDK19 control the dynamic transcription of selected genes in response to various signals have been shown be hijacked sustain hyperproliferation by solid liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic target. Here, we report discovery compound
Protein arginine methyltransferase 5 (PRMT5), which catalyzes the symmetric dimethylation of residues on target proteins, plays a critical role in gene expression regulation, RNA processing, and signal transduction. Aberrant PRMT5 activity has been implicated cancers other diseases, making it potential therapeutic target. Here, we report discovery methylthioadenosine (MTA) cooperative inhibitor. Compound 20 exhibited strong antiproliferation multiple MTAP-deleted cancer cell lines, excellent...
Fibroblast growth factor receptors (FGFRs) are established oncogenic drivers in various solid tumors. However, the approved FGFR inhibitors face challenges with acquired resistance and dose-limiting adverse effects associated FGFR1/4 inhibition, limiting therapeutic efficacy. Herein, we systematically explored linker electrophile moieties based on pyrrolopyrazine carboxamide core identified aniline α-fluoroacrylamide as an effective covalent warhead. Compound 10 potently inhibited FGFR2...
The dual inhibition of SIK2/3 has been considered as a potential treatment approach for MEF2C-high acute myeloid leukemia (AML). Although diverse scaffolds pan-SIK or inhibitors have reported, few them showed sufficient in vitro vivo antitumor activity. Based on the proposed binding mode hit molecule (7), chemical space solvent/P-loop region was explored via fragment growing/replacement, supported by generative chemistry platform. Further SAR exploration and ADME optimization led to...
Hematopoietic progenitor kinase 1 (HPK1) has emerged as an attractive target for immunotherapy due to its critical role in T cell activation and proliferation. The major challenge developing HPK1 inhibitors lies balancing selectivity, pharmacokinetic (PK) properties, therapeutic efficacy. In this study, we report a series of pyridine-2-carboxamide analogues demonstrating strong inhibitory activity enzymatic cellular assays, along with good selectivity. Among these analogues, compound
Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target breast cancer using PandaOmics, an AI-driven discovery platform. The synthetic lethal relationship tumor cell lines with CCNE1 amplification enhanced this rationale. Through structure-based drug design, we developed series novel, potent, highly selective inhibitors specifically targeting...
Fluoroalkylated quinoxlines with various groups were efficiently synthesized via a one-pot tandem Michael addition/azidation/cycloamination process. Under the mild and metal-free conditions, bis-imine intermediate (4a) was detected isolated for first time. KI played crucial role in this reaction. The mechanism described.
In the presence of KI and (diacetoxyiodo)benzene (PIDA), primary amines bearing an α‐hydrogen can be efficiently converted to fluoroalkylated imidazoles by reacting with alkynes sodium azide via a cascade Michael addition/azidation/cycloamination process. plays crucial role in this reaction generating iodine(I) species promote cyclization. Substrate scope was explored, application protocol demonstrated. Additionally, plausible mechanism proposed.
Hematopoietic progenitor kinase 1 (HPK1) negatively affects T cell activation and proliferation is a promising target for immunotherapy. Although HPK1 inhibitors have shown efficacy in preclinical models, none been approved clinical use. One significant challenge developing an inhibitor the difficulty designing potent with good selectivity pharmacokinetic properties. Here, we report series of spiro potency selectivity. Specifically, compound