Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors
Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors
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DOI：
10.1073/pnas.1207759109
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发表时间：
2012-11-06
影响因子：
11.1
通讯作者：
Kania, Robert S.
中科院分区：
文献类型：
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作者：
McTigue, Michele;Murray, Brion William;Kania, Robert S.
对临床开发中的化合物的分析表明，具有特殊物理性质和低剂量的配体有效分子在临床试验的各个阶段不太可能失败，批准后撤回较少，并且不太可能收到黑盒安全警告。然而，缺乏详细的并排检查的分子相互作用和性质内的单一药物类别。作为一类，VEGF受体酪氨酸激酶抑制剂（VEGFR TKI）已经改变了癌症治疗的前景，特别是在透明细胞肾细胞癌中，其与VEGF信号传导轴分子相关。尽管分子靶点的作用明确，但这种经过验证的药物类别的成员分子在可比的肾细胞癌临床研究中表现出不同的临床疗效和安全性。活性VEGFR TKI之间的首项头对头随机III期比较研究证实了临床性能的显著差异[Rini BI，et al.（2011）Lancet 378：193-1939]。为了阐明如何实现基本的药物效力-效率并影响VEGFR TKI类别内的分化，我们使用包括重要的内膜结构域的VEGFR 2 TK构建体测定了药物-激酶复合物的效力、时间依赖性、选择性和X射线结构。总的来说，这些研究阐明了独特的药物-激酶相互作用，这些相互作用依赖于不同的质膜结构域构象，导致显著的效力和配体效率差异。所确定的结构趋势与体外测量结果一致，这很好地转化为临床性能，强调了可能广泛适用于前瞻性药物设计以获得最佳体内性能的原则。
Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193-1939]. To elucidate how fundamental drug potency-efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug-kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug-kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.