Synergistic Inhibitors of CREB-mediated Gene Transcription

公共摘要 本申请的目的是开发CREB介导的基因的协同抑制剂， 转录。环腺苷酸反应元件结合蛋白（CREB）是一个43 kD的核内蛋白， 转录因子它的转录活性主要依赖于磷酸化。 Ser 133是由细胞外信号包括生长因子和激素诱导的。 CREB在不同器官的肿瘤组织中过表达和/或过激活 与正常组织相比。CREB的转录活性被激活， 通过多种蛋白激酶包括蛋白激酶A在Ser 133磷酸化 (PKA)促分裂原活化蛋白激酶（MAPK）、蛋白激酶B（PKB/Akt）和 蛋白核糖体S6激酶（pp 90 RSK）。一旦磷酸化，CREB可以与 CREB结合蛋白（CBP）及其parabolic p300募集其他成分， 启动CREB依赖性基因 转录。CREB在正常细胞中的磷酸化受到严格的调节， 动态的到目前为止，已经鉴定出三种蛋白磷酸酶能够 去除CREB中的磷酸盐以减弱其转录活性。它们是蛋白质 磷酸酶1（PP 1）、蛋白磷酸酶2A（PP 2A）和磷酸酶和张力蛋白 同源物（PTEN）。从机制上讲，激酶通常在癌细胞中过度活化 而磷酸酶通常在癌细胞中失活。因此，CREB 与正常细胞相比，在癌细胞中经常被过度激活。高表达和/或 CREB的激活与癌症患者的预后较差相关。临床前 研究已经证实CREB是各种癌症的有吸引力的靶点。我们最近 鉴定了作为CREB的小分子抑制剂或增效剂的各种化学型， 在抑制CREB介导的基因转录中表现出协同活性。在这 应用，我们将进一步开发这些抑制剂和增效剂作为协同 CREB介导的基因转录抑制剂。我们将进一步研究它们的作用机制。 作用和协同抗乳腺癌活性。完成了 拟议的研究将为CREB调节机制提供新的见解， 提供潜在的癌症治疗剂。

Public Abstract The goal of this application is to develop synergistic inhibitors of CREB-mediated gene transcription. Cyclic-AMP-response element binding protein (CREB) is a 43 kD nuclear transcription factor. Its transcription activity is critically dependent on phosphorylation on Ser133 to be induced by extracellular signals including growth factors and hormones. CREB is overexpressed and/or overactivated in tumor tissues of different organs compared to normal tissue. CREB's transcription activity is activated upon phosphorylation at Ser133 by a variety of protein kinases including protein kinase A (PKA), mitogen-activated protein kinases (MAPKs), protein kinase B (PKB/Akt) and protein ribosomal S6 kinase (pp90RSK). Once phosphorylated, CREB can bind with CREB-binding protein (CBP) and its paralog p300 to recruit other components in the transcriptional machinery to the CREB promoter to initiate CREB-dependent gene transcription. CREB's phosphorylation in normal cells is tightly regulated and very dynamic. Until now, three protein phosphatases have been identified to be able to remove the phosphate from CREB to attenuate its transcription activity. They are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN). Mechanistically, the kinases are often overactivated in cancer cells while the phosphatases are often inactivated in cancer cells. As a consequence, CREB is often overactivated in cancer cells compared to normal cells. Higher expression and/or activation of CREB is associated with poorer prognosis in cancer patients. Preclinical studies have validated CREB as an appealing target for various cancers. We recently identified various chemotypes as small molecule inhibitors of CREB or potentiators to exhibit synergistic activity in inhibiting CREB-mediated gene transcription. In this application, we will further develop these inhibitors and potentiators as synergistic inhibitors of CREB-mediated gene transcription. We will further study their mechanism of action and synergistic anti-breast cancer activity in vitro and in vivo. Accomplishing the proposed studies will provide novel insights into the mechanism of CREB regulation and provide potential cancer therapeutics.