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Identification of Thieno[3,2- d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3

Authors
 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 
Citation
 JOURNAL OF MEDICINAL CHEMISTRY, Vol.64(16) : 11934-11957, 2021-07 
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
 0022-2623 
Issue Date
2021-07
MeSH
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 ; Mice, 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 ; Thiophenes / chemical synthesis ; Thiophenes / metabolism ; Thiophenes / pharmacology ; Thiophenes / therapeutic use* ; Xenograft Model Antitumor Assays ; fms-Like Tyrosine Kinase 3 / antagonists & inhibitors ; fms-Like Tyrosine Kinase 3 / metabolism
Abstract
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.
Full Text
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00459
DOI
10.1021/acs.jmedchem.1c00459
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
Cho, Hanna(조한나)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187089
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