DISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINS

染色质是组蛋白、RNA和DNA的复合物，其有效地将基因组包装在其中。 每个人体细胞通过组蛋白的翻译后修饰（PTM）调节染色质可及性 作为药物干预“写”、“阅读”和“擦除”的机会， 这些PTM都是重要的。大多数PTM的生物学后果是由于它们招募了 通过PTM直接促进的蛋白质-蛋白质相互作用调节机制。的结合结构域 参与染色质上PTM识别的分子被称为“阅读器”。 该计划的首要目标是开发CBX阅读器的体内化学探针 Polycomb repressive complex 1（PRC1）有八个人CBX染色体结构域， 作为两种主要染色质抑制复合物内的甲基赖氨酸（Kme）识别结构域（阅读器）， 在高等真核生物中是保守的。CBX蛋白1、3和5与异染色质相关 蛋白1（HP 1）复合物。它们的Kme结合活性是染色质的压实和抑制所必需的， 带有组蛋白H3，赖氨酸9三甲基（H3 K9 me 3）标记。CBX蛋白2、4、6、7和8与 结合H3 K27 me 3标记的PRC 1。在整个过程中，基因组位点的适当抑制至关重要 生物体发育和分化，HP 1和Polycomb途径的失调涉及许多 疾病状态和靶向PRC 1的体内化学探针将是靶向通路的一流试剂 具有高度的疾病相关性，也将代表一种独特的工具，以探索复杂的体内Polycomb生物学 系统. 这项工作的成果将是一种高质量的体内化学探针， 学术界，与CBX读者相比， PRC 1催化该靶点向肿瘤学新治疗发现的进展， 其它疾病

Chromatin is the complex of histone proteins, RNA, and DNA that efficiently packages the genome within each human cell. The regulation of chromatin accessibility via post-translational modifications (PTM) of histones is of great current interest as opportunities for pharmacological intervention in the ‘writing’, ‘reading’ and ‘erasing’ of these PTMs are significant. The biological consequences of most PTMs result from their recruitment of regulatory machinery via protein-protein interactions directly facilitated by the PTM. The binding domains involved in PTM recognition on chromatin are referred to as “readers”. The overarching objective of this program is to develop an in vivo chemical probe of the CBX reader domains of Polycomb repressive complex 1 (PRC1). There are eight human CBX chromodomains that function as methyl-lysine (Kme) recognition domains (readers) within the two major chromatin repressive complexes that are conserved across higher eukaryotes. CBX proteins 1, 3 and 5 are associated with the heterochromatin protein 1 (HP1) complex. Their Kme binding activity is required for compaction and repression of chromatin that bears the histone H3, lysine 9 trimethyl (H3K9me3) mark. CBX proteins 2, 4, 6, 7, and 8 are associated with the PRC1 which binds the H3K27me3 mark. As appropriate repression of genomic loci is critical throughout organismal development and differentiation, dysregulation of HP1 and Polycomb pathways is implicated in many disease states and an in vivo chemical probe targeting PRC1 would be a first-in-class agent targeting a pathway of high disease relevance and would also represent a unique tool to explore Polycomb biology in complex in vivo systems. The deliverable from this effort will be a high-quality in vivo chemical probe, freely available to the academic community, with confirmed activity and well characterized mechanism versus the CBX readers of PRC1 to catalyze progression of this target toward new therapeutic discoveries in oncology and, potentially, other diseases.