Gold-based pharmacophore synthetic strategies as a basis for transcription factor modulator discovery

项目总结/摘要-项目1 转录因子（TF）失调是包括癌症在内的许多疾病的基础;然而，选择性转录因子（TF）失调是一个非常重要的问题。 用小分子探针/引导物靶向TF仍然是难以捉摸的。我们的研究计划旨在利用 金基[Au（I）和Au（III）]配合物作为TF基础的独特空间性质和化学反应性 探针/先导调制器发现。具体而言，我们寻求开发新颖有效的反应方法，以快速 构建不同的基于Au的药效团库，并利用这些独特的化合物集， 简化的筛选策略，以发现模型致癌转录因子c的选择性调节剂， MYC。这项研究将开发一个可推广的平台，以靶向蛋白质-蛋白质等“不可治疗”的靶点 界面或TF，通过两种方式使用“笼状”金中心：i）直接将金连接到特定氨基酸，或ii） 通过还原消除转移配位配体共价修饰特定氨基酸， 类似于由过渡金属基催化剂进行的化学反应。这些研究将扩大稳定的 金配体通过优化Au催化过程，推进我们对可调反应性的理解 和生物正交性的Au基药效团，并可能设置一个通用的战略阶段， 靶向“不可用”蛋白质。拟议研究的一个主要创新是有可能极大地改变， 通过共价修饰，蛋白质表面结构/电子学，从而影响功能。 CPRI的指导和研究支持核心将以一些关键方式进一步促进这一项目。 具体来说，计算核心将有助于开发新的预测结构-活性 基于Au的探针的SAR模型和计算c-MYC/MAX-配体结构模型，以指导 探针设计;翻译核心将促进分析开发、验证和实施（以及 最终首先在动物评估中进行，包括PK和ADMET）;以及COBRE分子医学 有机合成核心将战略性地支持配体合成/扩大规模。这也将通过一个 COBRE导师团队在转录因子先导发现、癌症生物学和 制药科学

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Transcription factor (TF) deregulation underlies numerous diseases including cancer; however, the selective targeting of TFs with small molecule probes/leads remains elusive. Our research program seeks to exploit the unique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for TF probe/lead modulator discovery. Specifically, we seek to develop novel and efficient reaction methods to rapidly construct diverse Au-based pharmacophore libraries and to leverage these unique compound sets, and a streamlined screening strategy, to discover selective modulators of the model oncogenic transcription factor c- MYC. This study will develop a generalizable platform to target ‘undruggable’ targets such as protein-protein interfaces or TFs, using ‘caged’ gold centers via two ways: i) directly ligate gold to specific amino acids, or ii) covalently modify specific amino acids by transfer of coordinated ligands via reductive elimination in a manner similar to chemistry performed by transition metal-based catalysts. The studies will extend the breadth of stable gold ligands through optimization of Au catalytic processes, advance our understanding of the tunable reactivity and bioorthogonality of Au-based pharmacophores and potentially set the stage for a generalized strategy to target ‘undruggable’ proteins. A primary innovation of the proposed studies is the potential to dramatically alter, via covalent modification, protein surface structure/electronics and thereby influence function. CPRI mentorship and research support cores will further facilitate this project in a number of key ways. Specifically, the Computational Core will assist in the development of new predictive structure-activity relationship (SAR) models for Au-based probes and computational c-MYC/MAX-ligand structural models to guide probe design; the Translational Core will facilitate assay development, validation, and implementation (and eventually first in animal assessments including PK and ADMET); and the COBRE for Molecular Medicine’s Organic Synthesis Core will strategically support ligand synthesis/scale-up. This will also be augmented by a COBRE mentorship team with extensive expertise in transcription factor lead discovery, cancer biology, and pharmaceutical science.