Effective targeting survivin dimerization interface with small molecule inhibitors

摘要 许多蛋白质已被确定为药物发现的靶点，但被认为是“不可药用的”。 因为它们缺乏酶活性。这一教条消除了许多理想的目标，因此，它放慢了速度 在推动体内化学探针和潜在药物的发现方面取得了进展。我们的长期目标是 开发新的方法来更好地靶向这些“不可药用”蛋白质的相互作用界面。最近我们 提出了一种新的概念和自动计算方法来识别界面疏水核 作为成核位点驱动蛋白质二聚化的残基。在初步研究中，我们证明 我们已经成功地鉴定和验证了一种热门化合物LQZ-7和几种活性类似物， 用两种不同的化学型命中靶向二聚体界面中的关键二聚化核心残基， 生存素在本申请中，我们建议使用药物化学来进一步优化这些抑制剂， 进行体外和体内试验，以确定进一步开发的先导化合物。为此我们 将在资助期内实现以下具体目标：（1）对两种化学类型进行化学修饰 用于先导物鉴定和优化;（2）使用生物化学分析新合成的类似物， 生物物理和基于细胞的测定;和（3）确定临床前药代动力学、毒性和体内功效 潜在的铅化合物。这项研究的结果不仅会产生潜在的新的体内化学物质， 探针和药物直接靶向生存素的二聚化结构域，而且还提供了新的证据， 一般来说，这种方法可以应用于许多其他“不可药用”的蛋白质二聚体，这些蛋白质二聚体可能具有 对未来药物发现过程和疾病管理产生重大而深远的影响。

Abstract Many proteins have been identified as targets for drug discovery but are considered “undruggable” because they lack enzymatic activities. This dogma has eliminated many ideal targets and, thus, it has slowed down progress in fueling discovery of in-vivo chemical probes and potential drugs. Our long-term goal is to develop new approaches to better target the interaction interface of these “undruggable” proteins. Recently, we developed a novel concept and an automated computational method to identify interfacial hydrophobic core residues that serve as nucleation sites to drive protein dimerization. In preliminary studies, we demonstrate that we have successfully identified and validated a hit compound, LQZ-7, and several active analogues of the hit with two different chemotypes targeting the critical dimerization core residues in the interface of dimeric survivin. In this application, we propose to use medicinal chemistry to further optimize these inhibitors and perform both in-vitro and in-vivo assays to identify lead compounds for further development. To this end, we will accomplish the following specific aims within the funding period: (1) to chemically modify both chemotypes for lead identification and optimization; (2) to analyze newly synthesized analogues using biochemical, biophysical, and cell-based assays; and (3) to determine preclinical pharmacokinetics, toxicity, and in-vivo efficacy of potential lead compounds. The outcome of this study will not only result in potential new in-vivo chemical probes and drugs by directly targeting the dimerization domain of survivin, but also provide evidence for a new approach that can be applied to many other “undruggable” protein dimers in general, which likely will have a significant and profound impact on future drug discovery process and disease management.