Novel Celecoxib Derivatives as Chemopreventive Agents

描述（由申请人提供）：本项目旨在开展开创性的转化研究，开发一类新的分子靶向药物，用于预防前列腺癌。这些药物是在Pl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，其原理是多方面的。首先，塞来昔布及其新型衍生物的细胞周期阻滞、细胞凋亡激活和血管生成抑制能力不依赖于COX-2抑制，而主要是通过抑制磷酸肌醇依赖性激酶-1 (PDK-1)/Akt信号传导。前列腺癌细胞的凋亡诱导与雄激素依赖性、p53功能状态和Bcl-2表达水平无关。其次，PDK-1/Akt信号在前列腺肿瘤中构成性激活，其失调提供了前列腺肿瘤细胞耐受生存因子退出并形成雄激素非依赖性表型的机制。这一信号通路在癌变过程中的生物学重要性为其抑制前列腺癌提供了分子理论依据。第三，这些药物可以口服，并且具有可控的毒理学特征，与慢性治疗相适应。我们假设在血清浓度为5-10微米的剂量下使用PDK-1/Akt信号抑制剂可以预防前列腺癌的发生或延缓癌变的进展。该建议包括两个具体目标，其结果将为我们开发新型分子靶向化学预防剂的长期目标提供强有力的理论依据。第一个具体目的是评估OSU-02067在n -甲基-n -亚硝基脲雄激素诱导Wistar-Unilever大鼠前列腺癌模型中的化学预防作用。OSU-02067是一种结构优化的衍生物，可抑制PDK-1/Akt信号通路，但不具有COX-2活性。第二个具体目的是评估OSU-01010的化学预防作用，以解决同时抑制COX-2和PDK-1/Akt信号是否会对化学预防产生协同作用的问题。OSU-01010是一种双功能衍生物，与塞来昔布相比，对COX-2和PDK-1/Akt信号传导具有增强的抑制活性。与此同时，我们将在未经致癌物处理的无肿瘤动物中检测这些化合物长期口服治疗的安全性。

DESCRIPTION (provided by applicant): This project is aimed at conducting seminal translational research to develop a new class of molecularly targeted agents for prostate cancer prevention. These agents were developed in the Pl's laboratory by using celecoxib as a molecular starting point via computer modeling-based structural analysis, of which the rationale is multifold. First, the ability of celecoxib and its novel derivatives to arrest cell cycle, activate apoptosis, and inhibit angiogenesis is independent of COX-2 inhibition, and is primarily attributable to the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling. The apoptosis induction in prostate cancer cells is irrespective of androgen dependency, p53 functional status, and Bcl-2 expression levels. Second, PDK-1/Akt signaling is constitutively activated in prostate tumors, and its dysregulation furnishes a mechanism whereby prostate tumor cells withstand the withdrawal of survival factors, and develop an androgen-independent phenotype. The biological importance of this signaling pathway in carcinogenesis provides a molecular rationale to justify its inhibition as a viable approach to prostate cancer prevention. Third, these agents can be orally dosed, and have manageable toxicological profiles compatible with chronic treatment. We hypothesize that the PDK-1/Akt signaling inhibitor administered at doses providing serum concentrations of 5-10 microM will result in preventing the onset of prostate cancer or delaying the progression of carcinogenesis. This proposal consists of two specific aims, of which the results will provide a strong rationale for our long-term goal to develop novel molecularly targeted chemopreventive agents. The first specific aim is to assess the chemopreventive efficacy of OSU-02067, a structurally optimized derivative in inhibiting PDK-1/Akt signaling with no COX-2 activity, in the N-methyI-N-nitrosourea androgen induced model of prostate carcinogenesis in Wistar-Unilever rats. The second specific aim is to assess the chemopreventive effect of OSU-01010 to addrerss the issue of whether concurrent inhibition of COX-2 and PDK-1/Akt signaling will provide a synergistic effect on chemoprevention. OSU-01010 is a dual function derivative that displays enahnced inhibitory activities against both COX-2 and PDK-1/Akt signaling as compared to celecoxib. In parallel, we will examine the safety of chronic oral treatment with these compounds in non-carcinogen-treated tumor-free animals.