دورية أكاديمية
Identification of Thieno[3,2- d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3
| العنوان: | Identification of Thieno[3,2- d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3 |
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| المساهمون: | Hanna Cho, Injae Shin, Hojong Yoon, Eunhye Jeon, Jiwon Lee, Younghoon Kim, SeongShick Ryu, Chiman Song, Nam Hoon Kwon, Youngji Moon, Sunghoon Kim, Nam Doo Kim, Hwan Geun Choi, Taebo Sim, Sim, Taebo |
| بيانات النشر: | American Chemical Society |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Animals, Antineoplastic Agents / chemical synthesis, Antineoplastic Agents / metabolism, Antineoplastic Agents / pharmacology, Antineoplastic Agents / therapeutic use, Cell Line, Tumor, Drug Screening Assays, Antitumor, Female, Focal Adhesion Kinase 1 / antagonists & inhibitors, Focal Adhesion Kinase 1 / metabolism, Humans, Mice, Inbred BALB C, Nude, Molecular Docking Simulation, Molecular Structure, Neoplasm Metastasis / prevention & control, Neoplasms / drug therapy, Phosphorylation / drug effects, Protein Kinase Inhibitors / chemical synthesis, Protein Kinase Inhibitors / metabolism, Protein Kinase Inhibitors / pharmacology, Protein Kinase Inhibitors / therapeutic use, Pyrimidines / chemical synthesis, Pyrimidines / metabolism, Pyrimidines / pharmacology, Pyrimidines / therapeutic use, Structure-Activity Relationship |
| الوصف: | 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. ; restriction |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0022-2623 1520-4804 |
| العلاقة: | JOURNAL OF MEDICINAL CHEMISTRY; J01588; OAK-2021-08342; https://ir.ymlib.yonsei.ac.kr/handle/22282913/187089Test; T202105027; JOURNAL OF MEDICINAL CHEMISTRY, Vol.64(16) : 11934-11957, 2021-07 |
| DOI: | 10.1021/acs.jmedchem.1c00459 |
| الإتاحة: | https://doi.org/10.1021/acs.jmedchem.1c00459Test https://ir.ymlib.yonsei.ac.kr/handle/22282913/187089Test |
| حقوق: | CC BY-NC-ND 2.0 KR |
| رقم الانضمام: | edsbas.E4376CFC |
| قاعدة البيانات: | BASE |
| تدمد: | 00222623 15204804 |
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| DOI: | 10.1021/acs.jmedchem.1c00459 |