70764-02-2Relevant academic research and scientific papers
Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold
Kissau, Lars,Stahl, Petra,Mazitschek, Ralph,Giannis, Athannasios,Waldmann, Herbert
, p. 2917 - 2931 (2007/10/03)
Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC50s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.
Natural product derived receptor tyrosine kinase inhibitors: Identification of IGF1R, Tie-2, and VEGFR-3 inhibitors
Stahl, Petra,Kissau, Lars,Mazitschek, Ralph,Giannis, Athanassios,Waldmann, Herbert
, p. 1174 - 1178 (2007/10/03)
Blood and lymph vessel growth is regulated by Tie-2 and the VEGFR-3 receptor tyrosine kinases. These proteins also play major roles in the growth and metastasis of cancers. A novel class of inhibitors of these signal-transducing proteins, and of the IGF1R
Isolation, Synthesis, Structure-Activity Relationships of Bioactive Benzoquinones from Miconia lepidota from the Suriname Rainforest
Gunatilaka, A. A. Leslie,Berger, John M.,Evans, Randy,Miller, James S.,Wisse, Jan H.,Neddermann, Kim M.,Bursuker, Isia,Kingston, David G. I.
, p. 2 - 5 (2007/10/03)
Bioactivity-directed fractionation of an EtOAc extract from the leaves of Miconia lepidota afforded the two benzoquinones 2-methoxy-6-heptyl-1,4-benzoquinone (1) and 2-methoxy-6-pentyl-1,4-benzoquinone (primin) (2). This is the first reported isolation of
