Novel Celecoxib Derivatives as Chemopreventive Agents

描述（由申请人提供）：该项目旨在进行开创性的转化研究，以开发一类新的前列腺癌预防分子靶向药物。这些药物是在PI的实验室中通过使用塞来昔布作为分子起点，通过基于计算机建模的结构分析开发的，其原理是多方面的。首先，塞来昔布及其新型衍生物阻滞细胞周期、激活细胞凋亡和抑制血管生成的能力不依赖于考克斯-2抑制，并且主要归因于磷酸肌醇依赖性激酶-1（PDK-1）/Akt信号传导的抑制。前列腺癌细胞中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被组成性激活，其失调证实了前列腺肿瘤细胞耐受生存因子撤回的机制，并发展出雄激素非依赖性表型。这种信号通路在致癌作用中的生物学重要性提供了分子理论基础来证明其抑制作为预防前列腺癌的可行方法是合理的。第三，这些药剂可以口服给药，并且具有与慢性治疗相容的可管理的毒理学特征。我们假设，PDK-1/Akt信号传导抑制剂以提供5-10 μ M血清浓度的剂量施用将导致预防前列腺癌的发作或延迟癌发生的进展。这个建议包括两个具体的目标，其中的结果将提供一个强有力的理由，我们的长期目标，开发新的分子靶向化学预防剂。第一个具体目的是评估OSU-02067的化学预防功效，OSU-02067是一种在Wistar-Unilever大鼠中N-甲基-N-亚硝基脲雄激素诱导的前列腺癌发生模型中抑制PDK-1/Akt信号传导而无考克斯-2活性的结构优化衍生物。第二个具体目的是评估OSU-01010的化学预防作用，以解决考克斯-2和PDK-1/Akt信号传导的同时抑制是否会对化学预防提供协同作用的问题。OSU-01010是一种双重功能衍生物，与塞来昔布相比，对考克斯-2和PDK-1/Akt信号传导的抑制活性增强。同时，我们将在非致癌物处理的无肿瘤动物中检查这些化合物的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.