Structural Optimization of Celecoxib for Chemoprevention

用于化学预防的塞来昔布的结构优化

• 批准号: 6737327
• 负责人: WOAN-RU M SHIEH
• 金额: $ 12.84万
• 依托单位: CELLSIGNALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737327
• 关键词: analog; antineoplastics; apoptosis; biological signal transduction; biomarker; cancer prevention; cell line; cell proliferation; chemical structure; chemical synthesis; chemoprevention; drug design /synthesis /production; kinase inhibitor; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; prostate neoplasms; serine threonine protein kinase

DESCRIPTION (provided by applicant): This project is aimed at developing a novel class of molecularly targeted agents for cancer prevention. The lead compound OSU-02067 was developed in our laboratory by using celecoxib as a molecular starting point via computer modeling-based structural analysis. Previously, we demonstrated that the ability of celecoxib to arrest cell cycle, activate apoptosis, and inhibit angiogenesis is independent of cyclooxygenase-2 (COX-2) inhibition, and is primarily attributable to the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling. The biological importance of the PDK-1/Akt signaling pathway in carcinogenesis provides a molecular rationale to justify its inhibition as a viable strategy to chemoprevention. Consequently, we have synthesized over one hundred celecoxib derivatives for testing PDK-1 inhibitory activity and apoptosisinducing activity in PC-3 human androgen-independent prostate cancer cells. In vitro and in vivo testing of a panel of lead compounds led to the selection of a structurally optimized agent OSU-02067. OSU-02067 inhibits the proliferation of PC-3 prostate cancer cells as low as 0.5 microM (vis-a-vis 30 microM for celecoxib), and is effective in inhibiting the growth of PC-3 xenograft in nude mice. More noteworthy is that it could be orally dosed to provide serum concentrations exceeding 20 microM without demonstrable toxicity, compatible with chronic use for chemoprevention. Thus, this proposal consists of two pecific aims. Aim 1 is to use OSU-02067 as a lead to continue the development of the 3rd-generation celecoxib derivatives with enhanced activity in inhibiting PDK-1/Akt signaling. Based on our working model, we will focus on enhancing the electronegative potential surrounding the heterocyclic system to augment its interactions with the enzyme pocket. Our goal is to lower the IC50 for inhibiting PDK-1/Akt signaling to the sub-microM level. Aim 2 is to assess the in vitro antitumor effect of OSU-02067 and selected 3rd-generation analogues in different cancer cell lines. Akt kinase activities and various biomarkers pertinent to cell cycle arrest and apoptosis will be examined to understand the underlying mechanism. These findings will serve as the basis for submission of a Phase II grant proposal in support of our long-term goal to develop a novel class of agents that target PDK-1/Akt signaling for cancer prevention.

项目描述（由申请人提供）：本项目旨在开发一类新型的分子靶向癌症预防药物。先导化合物OSU-02067是在我们实验室通过基于计算机建模的结构分析，以塞来昔布为分子起点开发的。先前，我们证明了塞来昔布的细胞周期阻滞、细胞凋亡激活和血管生成抑制能力不依赖于环氧化酶-2 （COX-2）抑制，而主要归因于磷酸肌醇依赖激酶-1 (PDK-1)/Akt信号的抑制。PDK-1/Akt信号通路在癌变过程中的生物学重要性为其抑制作为化学预防的可行策略提供了分子理论依据。因此，我们已经合成了一百多种塞来昔布衍生物，用于测试PC-3人雄激素非依赖性前列腺癌细胞的PDK-1抑制活性和诱导凋亡活性。体外和体内测试的一组先导化合物导致了结构优化剂OSU-02067的选择。OSU-02067对PC-3前列腺癌细胞的增殖抑制作用低至0.5微米（塞来昔布为30微米），并能有效抑制裸鼠PC-3异种移植物的生长。更值得注意的是，它可以口服给药，提供超过20微米的血清浓度，而没有明显的毒性，适合用于化学预防的慢性使用。因此，这项建议包括两个具体目标。目的1是以OSU-02067为先导，继续开发具有增强抑制PDK-1/Akt信号活性的第三代塞来昔布衍生物。基于我们的工作模型，我们将专注于增强杂环体系周围的电负性电位，以增强其与酶袋的相互作用。我们的目标是将抑制PDK-1/Akt信号传导的IC50降低到亚微米水平。目的2：评价OSU-02067及其第三代类似物在不同肿瘤细胞系中的体外抗肿瘤作用。Akt激酶活性和与细胞周期阻滞和凋亡相关的各种生物标志物将被检查以了解潜在的机制。这些发现将作为提交II期拨款提案的基础，以支持我们开发一类针对PDK-1/Akt信号的新型药物以预防癌症的长期目标。