BIOMAT Database Logo BIOMAT Database Logo

Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment. 2018

Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.

UI MeSH Term Description Entries
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000081082 Phosphoinositide-3 Kinase Inhibitors Agents that inhibit PHOSPHOINOSITIDE-3 KINASE activity. Phosphoinositide-3 Kinase Inhibitor,Inhibitor, Phosphoinositide-3 Kinase,Inhibitors, Phosphoinositide-3 Kinase,Kinase Inhibitor, Phosphoinositide-3,Kinase Inhibitors, Phosphoinositide-3,Phosphoinositide 3 Kinase Inhibitor,Phosphoinositide 3 Kinase Inhibitors
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

Related Publications

Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery and optimization of 4-pyrazolyl-2-aminopyrimidine derivatives as potent spleen tyrosine kinase (SYK) inhibitors.
April 2024, European journal of medicinal chemistry,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors.
April 2010, Journal of medicinal chemistry,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase.
April 2014, Bioorganic & medicinal chemistry letters,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors.
February 2020, Bioorganic & medicinal chemistry letters,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery of 2-Amino-3-cyanothiophene Derivatives as Potent STAT3 Inhibitors for the Treatment of Osteosarcoma Growth and Metastasis.
May 2022, Journal of medicinal chemistry,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.
July 2021, Bioorganic & medicinal chemistry letters,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery of 2-arylamino-4-(1-methyl-3-isopropylsulfonyl-4-pyrazol-amino)pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
September 2015, Bioorganic & medicinal chemistry letters,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery and optimization of new 6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives as potent influenza virus PAN inhibitors.
January 2022, European journal of medicinal chemistry,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.
June 2023, Journal of medicinal chemistry,
Songwen Lin, and Chunyang Wang, and Ming Ji, and Deyu Wu, and Yuanhao Lv, and Kehui Zhang, and Yi Dong, and Jing Jin, and Jiajing Chen, and Jingbo Zhang, and Li Sheng, and Yan Li, and Xiaoguang Chen, and Heng Xu
Discovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid Arthritis.
July 2019, Journal of medicinal chemistry,
Copied contents to your clipboard!