Identification of Thieno[3,2-d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3
Copyright policy )Identification of Thieno[3,2-d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3
Focal adhesion kinase (FAK) is overexpressed in highly invasive and metastatic cancers. To identify novel FAK inhibitors, we designed and synthesized various thieno[3,2-d]pyrimidine derivatives. An intensive structure-activity relationship (SAR) study led to the identification of 26 as a lead. Moreover, 26, a multitargeted kinase inhibitor, possesses excellent potencies against FLT3 mutants as well as FAK. Gratifyingly, 26 remarkably inhibits recalcitrant FLT3 mutants, including F691L, that cause drug resistance. Importantly, 26 is superior to PF-562271 in terms of apoptosis induction, anchorage-independent growth inhibition, and tumor burden reduction in the MDA-MB-231 xenograft mouse model. Also, 26 causes regression of tumor growth in the MV4-11 xenograft mouse model, indicating that it could be effective against acute myeloid leukemia (AML). Finally, in an orthotopic mouse model using MDA-MB-231, 26 remarkably prevents metastasis of orthotopic tumors to lymph nodes. Taken together, the results indicate that 26 possesses potential therapeutic value against highly invasive cancers and relapsed AML.
- Korea University Korea (Republic of)
- Korean Association Of Science and Technology Studies Korea (Republic of)
- University of California, San Diego United States
- Gangnam Severance Hospital Korea (Republic of)
- Yonsei University Medical Library Korea (Republic of)
Focal Adhesion Kinase 1 / antagonists & inhibitors, Thiophenes / pharmacology, Nude, Antineoplastic Agents / pharmacology, Drug Screening Assays, Mice, Protein Kinase Inhibitors / metabolism, Neoplasms, Pyrimidines / therapeutic use*, fms-Like Tyrosine Kinase 3 / metabolism, Antineoplastic Agents / chemical synthesis, Neoplasm Metastasis, Phosphorylation, Neoplasms / drug therapy*, Inbred BALB C, Antineoplastic Agents / metabolism, Pyrimidines / pharmacology, Mice, Inbred BALB C, Tumor, Molecular Structure, Focal Adhesion Kinase 1 / metabolism, Molecular Docking Simulation, Thiophenes / chemical synthesis, Female, Pyrimidines / metabolism, 570, Thiophenes / therapeutic use*, 610, Mice, Nude, fms-Like Tyrosine Kinase 3 / antagonists & inhibitors, Antineoplastic Agents, Neoplasm Metastasis / prevention & control, Thiophenes, Antineoplastic Agents / therapeutic use*, Thiophenes / metabolism, Cell Line, Protein Kinase Inhibitors / therapeutic use*, Structure-Activity Relationship, Cell Line, Tumor, Animals, Humans, Protein Kinase Inhibitors / chemical synthesis, Protein Kinase Inhibitors, Phosphorylation / drug effects, Protein Kinase Inhibitors / pharmacology, Antitumor, Xenograft Model Antitumor Assays, Pyrimidines, fms-Like Tyrosine Kinase 3, Focal Adhesion Kinase 1, Drug Screening Assays, Antitumor, Pyrimidines / chemical synthesis
Focal Adhesion Kinase 1 / antagonists & inhibitors, Thiophenes / pharmacology, Nude, Antineoplastic Agents / pharmacology, Drug Screening Assays, Mice, Protein Kinase Inhibitors / metabolism, Neoplasms, Pyrimidines / therapeutic use*, fms-Like Tyrosine Kinase 3 / metabolism, Antineoplastic Agents / chemical synthesis, Neoplasm Metastasis, Phosphorylation, Neoplasms / drug therapy*, Inbred BALB C, Antineoplastic Agents / metabolism, Pyrimidines / pharmacology, Mice, Inbred BALB C, Tumor, Molecular Structure, Focal Adhesion Kinase 1 / metabolism, Molecular Docking Simulation, Thiophenes / chemical synthesis, Female, Pyrimidines / metabolism, 570, Thiophenes / therapeutic use*, 610, Mice, Nude, fms-Like Tyrosine Kinase 3 / antagonists & inhibitors, Antineoplastic Agents, Neoplasm Metastasis / prevention & control, Thiophenes, Antineoplastic Agents / therapeutic use*, Thiophenes / metabolism, Cell Line, Protein Kinase Inhibitors / therapeutic use*, Structure-Activity Relationship, Cell Line, Tumor, Animals, Humans, Protein Kinase Inhibitors / chemical synthesis, Protein Kinase Inhibitors, Phosphorylation / drug effects, Protein Kinase Inhibitors / pharmacology, Antitumor, Xenograft Model Antitumor Assays, Pyrimidines, fms-Like Tyrosine Kinase 3, Focal Adhesion Kinase 1, Drug Screening Assays, Antitumor, Pyrimidines / chemical synthesis
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