Naturally Occurring Homoisoflavonoids as Potent Protein Tyrosine Kinases Inhibitors

Protein tyrosine kinases (PTK) have been recognized as promising therapeutic targets for a variety of human diseases. The development of new and more effective PTK inhibitors represents an attractive therapeutic strategy for cancer chemoprevention [1]. Here we report the identification of some potent c-Src tyrosine kinase inhibitors by an automated high-throughput screening (HTS) strategy based on the orthogonal-compound-mixing ELISA method [2]. Hematoxylin (1), the main component of the plant Heamatoxylon campechianum (Leguminosae) [3], stood out as one of the most remarkable c-Src inhibitors of a 32,200 compounds library. Further investigations revealed that hematoxylin is an ATP competitive broad-spectrum PTK inhibitor in vitro, with IC₅₀ values ranging from nanomolar to micromolar level. In addition, hematoxylin is also noted to inhibit the phosphorylation of PTK and arrest the downstream signaling pathways in cellular level. Moreover, other ten new homoisoflavonoids, together with sixteen known homoisoflavonoids and chalcones, were isolated from the stems of H. campechianum upon bioassay-guided fractionation for the purpose of seeking bioactive hematoxylin analogues. The structure-activity relationship of these compounds was further performed by assessing the PTK inhibitory potency with concurrent molecular docking simulation. Hematoxylin and its natural analogues were substantially validated to function as a new class of PTK inhibitors.

Acknowledgements: This work was financially supported by grants from the Ministry of Science and Technology (2004CB518902 and 2004CB518903). References: [1] Baselga J (2006) Science 312: 1175–1178. [2] Irby RB, Yeatman TJ (2000) Oncogene 19: 5636–5642. [3] Armstrong WP (1992) Pacific Horticulture 53: 38–43.