Kissau Lars, Stahl Petra, Mazitschek Ralph, Giannis Athannasios, Waldmann Herbert
Max-Planck-Institut für molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
J Med Chem. 2003 Jul 3;46(14):2917-31. doi: 10.1021/jm0307943.
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 IC(50)s 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.
受体酪氨酸激酶（RTKs），如Tie-2、IGF1R、Her-2/Neu、EGFR和VEGFR1 - 3在细胞生长和分化的控制中发挥着关键作用。抑制此类RTKs已成为当前抗癌药物开发的主要焦点，因此发现针对这些信号转导蛋白的新型抑制剂至关重要。我们最近提出了一个新颖的概念，即通过利用天然产物作为化合物库开发结构空间中经过生物学验证的起始点来改进命中发现过程。在这个概念中，天然产物被视为蛋白质结构域经过进化选择的配体，这些结构域在结构上保守但在基因上可移动。在此，我们报告从天然存在的Her-2/Neu激酶抑制剂nakijiquinone C衍生并基于此概念开发的新型高选择性VEGFR - 2和 - 3、Tie-2和IGF1R抑制剂的发现。基于天然产物的结构，合成了一个小库（74个成员），并研究其对具有高度相似ATP结合结构域的激酶的抑制作用。该库以高频率产生了IC(50)在低微摩尔范围内的抑制剂（74个中有7个）。特别地，发现了四种Tie-2抑制剂，Tie-2是一种在从现有血管形成新血管（血管生成）过程中起关键作用的激酶，并且被认为是抗肿瘤治疗中有前景的新靶点。这些结果支持了“结构域概念”。为了推进改进抑制剂的开发，进行了广泛的分子建模研究，包括构建VEGFR - 2和Tie-2的新同源模型。这些研究揭示了激酶结构中对于开发定制的受体酪氨酸激酶抑制剂至关重要的残基。
