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Naturally Occurring Homoisoflavonoids Function as Potent Protein Tyrosine Kinase Inhibitors by c-Src-Based High-Throughput Screening

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posted on 14.08.2008 by Li-Gen Lin, Hua Xie, Hong-Lin Li, Lin-Jiang Tong, Chun-Ping Tang, Chang-Qiang Ke, Qun-Fang Liu, Li-Ping Lin, Mei-Yu Geng, Hualiang Jiang, Wei-Min Zhao, Jian Ding, Yang Ye
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.

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