Novel Celecoxib Derivatives as Chemopreventive Agents

描述(申请人提供)：该项目旨在进行开创性的翻译研究，以开发一类用于前列腺癌预防的新型分子靶向制剂。这些药物是在PL的实验室中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，其理论基础是多重的。首先，塞来昔布及其新的衍生物阻止细胞周期、激活细胞凋亡和抑制血管生成的能力与COX-2的抑制无关，主要归因于对磷酸肌醇依赖的激酶-1(PDK-1)/Akt信号的抑制。前列腺癌细胞的凋亡诱导与雄激素依赖性、P53功能状态和Bcl2表达水平无关。第二，PDK-1/Akt信号在前列腺癌中被结构性激活，其异常调节提供了一种机制，使前列腺癌细胞能够抵抗生存因子的撤除，并发展出雄激素非依赖性表型。这一信号通路在致癌过程中的生物学重要性为其抑制前列腺癌预防提供了分子基础。第三，这些药物可以口服，并具有可管理的毒理学特征，与慢性治疗兼容。我们假设，在提供5-10微米的血清浓度的情况下，给予PDK-1/Akt信号抑制物剂量将导致预防前列腺癌的发生或延缓癌变的进展。这项提议包括两个具体的目标，其中的结果将为我们开发新型分子靶向化学预防药物的长期目标提供强有力的理论基础。第一个特异性目的是评价OSU-02067在N-甲基-N-亚硝脲雄激素诱导的大鼠前列腺癌模型中的化学预防效果。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信号通路是否会在化学预防中提供协同作用的问题。OSU-01010是一种双功能衍生物，与塞来昔布相比，它对COX-2和PDK-1/AKT信号具有更强的抑制活性。同时，我们将在非致癌物治疗的无肿瘤动物身上检查这些化合物的慢性口服治疗的安全性。

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.