DISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINS

染色质是组蛋白、rna和dna的复合体，它有效地将基因组包装在 每一个人类细胞。组蛋白翻译后修饰(PTM)对染色质可及性的调节 作为药物干预“写”、“读”和“擦”的机会，目前极具吸引力。 其中PTM意义重大。大多数PTM的生物学后果是由于它们招募了 通过由PTM直接促进的蛋白质-蛋白质相互作用的调控机制。结合结构域 参与PTM对染色质识别的人被称为“阅读器”。 该计划的首要目标是开发一种CBX阅读器的体内化学探针 多梳抑制复合体1的结构域(Prc1)。有八个人类CBX染色域发挥作用 作为甲基赖氨酸(KME)识别结构域(阅读器)在两个主要的染色质抑制复合体中 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 蛋白质1(HP1)复合体。它们的KME结合活性是紧致和抑制染色质所必需的 带有组蛋白H3，赖氨酸9三甲基(H3K9me3)标记。CBX蛋白2、4、6、7和8与 结合H3K27me3标记的Prc1。在整个过程中，适当地抑制基因组基因座是至关重要的 生物体的发育和分化，HP1和多梳通路的失调与许多 疾病状态和靶向Prc1的体内化学探针将是靶向途径的一流药物 具有很高的疾病相关性，也将是探索复杂体内多梳状生物学的独特工具 系统。 这一努力的成果将是一种高质量的体内化学探针，可免费提供给 学术界，与CBX读者相比，活动得到证实，机制得到很好的描述 Prc1催化这一靶向肿瘤学新的治疗发现的进展，并有可能， 其他疾病。

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.