Unraveling p300/CBP oncogenic signaling utilizing small molecule inhibitors and probes

这项研究计划旨在开发一种可靠且经济高效的生化分析方法，以确定组蛋白乙酰转移酶(HATS)p300和CBP的抑制剂和配体。此外，将使用化学上不同的化合物文库进行高通量筛选，以努力识别有效的小分子HAT抑制剂。最终目标是开发有效和特异的HAT抑制剂和工具化合物，以探索它们通过影响p300/CBP靶基因的稳定性和促进其降解来抑制其生物活性的可能性。特别是，人们希望发现可以破坏HAT介导的c-Myc激活的配体，以便使用多个癌细胞系(例如前列腺癌和黑色素瘤)来破译c-Myc相互作用组中的致癌作用。如果适用，打算进一步研究这些分子在动物模型中作为抗癌剂的潜在用途。这一研究方法还将探讨HAT抑制剂在抑制其他乙酰化依赖的癌基因转录因子如雄激素和雌激素受体方面的潜在用途，这将导致在癌症研究中的广泛应用。本研究有可能发现小分子p300/CBP抑制剂，以进一步了解HAT活性在肿瘤发生中的生物学影响，以及了解乙酰化在已知转录因子癌基因的致瘤性中的作用。

This research proposal aims to develop a robust and cost-efficient biochemical assay to identify inhibitors and ligands for the histone acetyltransferases (HATs) p300 and CBP. Furthermore, high throughput screens using chemically diverse compound libraries will be performed in an effort to identify potent small molecule HAT inhibitors. The ultimate goal is to develop effective and specific HAT inhibitors and tool compounds to probe their potential to inhibit the biological activity of p300/CBP target oncogenes by affecting their stability and inducing their enhanced degradation. In particular, it is desired to discover ligands which may disrupt the HAT-mediated c-Myc activation in order to decipher the oncogenic interactions within the c-Myc interactome using multiple cancer cell lines (e.g., prostate cancer and melanoma). If applicable further investigations with respect to the potential use of these molecules as anticancer agents in animal models are intended. This research approach will also investigate the potential use of HAT inhibitors in inhibiting other acetylation-dependent oncogenic transcription factors such as androgen and estrogen receptors, which can lead to broad applications in cancer research.This research has the potential to uncover small molecule p300/CBP inhibitors to further understand the biological impact of HAT activity in tumor development as well as in understanding the role of acetylation in the tumorigenicity of known transcription factor oncogenes.