Effective targeting survivin dimerization interface with small molecule inhibitors

有效靶向存活蛋白二聚化与小分子抑制剂的界面

• 批准号: 9989176
• 负责人: JingYuan Liu
• 金额: $ 34.5万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9989176
• 关键词: Adult; Affinity; Animal Model; Apoptosis; Apoptosis Inhibitor; Binding; Biochemical; Biological; Biological Assay; Biophysics; Cell Survival; Cells; Chemicals; Clinical; Collection; Computer Models; Computing Methodologies; Data; Development; Dimerization; Disease Management; Drug Kinetics; Drug Targeting; Funding; Future; Gene Family; Goals; Half-Life; Homo; Homodimerization; Human; Hydrophobicity; In Vitro; Knowledge; Lead; Libraries; Measurement; Mitotic; Mus; Normal tissue morphology; Outcome; Outcome Study; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Process; Property; Proteins; Quality Control; Resources; Role; Site; Specificity; Structure; Study models; System; Testing; Therapeutic; Toxic effect; Work; Xenograft procedure; analog; base; cancer cell; clinical development; design; dimer; drug discovery; improved; in silico; in vivo; inhibitor/antagonist; interfacial; lead optimization; member; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; screening; small molecule; small molecule inhibitor; survivin; therapeutically effective; tumor growth; tumor xenograft

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.

摘要 许多蛋白质已被确定为药物发现的靶点，但被认为是“不能下药的” 因为它们缺乏酶活性。这种教条消除了许多理想的目标，因此放慢了脚步。 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针对这些“不能下药的”蛋白质的相互作用界面。最近，我们 提出了识别界面疏水核的新概念和自动计算方法 残基是驱动蛋白质二聚化的成核位点。在初步研究中，我们证明了 我们已经成功地鉴定和验证了一种热门化合物LQZ-7，以及几种活性类似物 两种不同化学类型靶向二聚体界面临界二聚核残基的HIT 幸存者。在这一应用中，我们建议使用药物化学来进一步优化这些抑制剂和 进行体外和体内测试，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 用于铅的识别和优化；(2)使用生化方法分析新合成的类似物， 生物物理学和基于细胞的分析；以及(3)确定临床前药代动力学、毒性和体内疗效 潜在的先导化合物。这项研究的结果不仅将导致潜在的新的体内化学物质 通过探针和药物直接靶向Survivin的二聚化结构域，也为新的 一种方法，可以应用于许多其他“不能下药的”蛋白质二聚体，这可能会有一个 对未来的药物发现过程和疾病管理产生重大而深远的影响。