Naturally occurring homoisoflavonoids function as potent protein tyrosine kinase inhibitors by c-Src-based high-throughput screening.
Protein tyrosine kinase (PTK) inhibitors represent emerging therapeutics for cancer chemoprevention. In our study, hematoxylin (26) was identified as one of the most remarkable c-Src inhibitors in an orthogonal compound-mixing library (32200 compounds) by using an ELISA-based automated high-throughput screening (HTS) strategy. Interestingly, hematoxylin was found to be an ATP competitive broad-spectrum PTK inhibitor in vitro, with IC50 values ranging from nanomolar to micromolar level. Further studies showed that such inhibition was associated with the PTK phosphorylation and subsequent downstream signaling pathways. The structure-activity relationship assessment of the PTK inhibitory potency of hematoxylin analogues isolated from Heamatoxylon campechianum was in good agreement with the result of concurrent molecular docking simulation: the catechol moiety in ring A and the hematoxylin-like three-dimensional structure were essential for c-Src-targeted activities. Hematoxylin and its natural analogues were substantially validated to function as a new class of PTK inhibitors.
Lin
Li-Gen
LG
Department of Natural Products Chemistry, Division of Anti-tumor Pharmacology and Drug Discovery, Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Xie
Hua
H
Li
Hong-Lin
HL
Tong
Lin-Jiang
LJ
Tang
Chun-Ping
CP
Ke
Chang-Qiang
CQ
Liu
Qun-Fang
QF
Lin
Li-Ping
LP
Geng
Mei-Yu
MY
Jiang
Hualiang
H
Zhao
Wei-Min
WM
Ding
Jian
J
Ye
Yang
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D045744:Cell Line, Tumor; D002474:Cell-Free System; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D007887:Fabaceae / Q000737:chemistry; D005419:Flavonoids / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology*; D006416:Hematoxylin / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D019061:src-Family Kinases; D006416:Hematoxylin