Abstract：
:Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery.
journal_name
Bioorg Chemjournal_title
Bioorganic chemistryauthors
Wang R,Zhao X,Yu S,Chen Y,Cui H,Wu T,Hao C,Zhao D,Cheng Mdoi
10.1016/j.bioorg.2020.104092subject
Has Abstractpub_date
2020-09-01 00:00:00pages
104092eissn
0045-2068issn
1090-2120pii
S0045-2068(20)31389-4journal_volume
102pub_type
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