Phosphodiesterase 10A, a novel target for lung cancer chemoprevention

摘要 临床前、临床和流行病学研究提供了令人信服的证据， 非甾体抗炎药（NSAID）具有抗炎活性， 降低多种癌症类型（包括肺癌）的发病率和死亡风险。 不幸的是，长期使用非甾体抗炎药的化学预防和他们的潜在应用， 不推荐使用，因为可能会导致致命的副作用 从环氧合酶（考克斯）抑制和生理上重要的 兰丁然而，许多研究人员得出结论， 它们的COX活性的基础可能不需要考克斯抑制，这表明 开发更安全和更有效的癌症非COX抑制衍生物的可行性， 针对潜在的机制。我们已经广泛研究了 非甾体抗炎药舒林酸抑制肿瘤细胞生长，并已报道，这种活性是由环 鸟苷酸磷酸二酯酶（cGMP PDE）抑制和激活 cGMP/蛋白激酶G信号转导抑制致癌β-catenin/Tcf转录活性 以及驱动肿瘤细胞生长的关键蛋白质，如细胞周期蛋白D1和生存素的合成 增殖和生存。在这里，我们表明cGMP降解PDE同工酶，PDE 10A是一种 舒林酸的重要靶点，在肺肿瘤中升高，对肺肿瘤至关重要 细胞生长在分子模拟的指导下，使用PDE 10的晶体结构，我们合成了 一系列有效和选择性抑制肺肿瘤细胞生长的新型舒林酸衍生物 而不抑制考克斯-1或考克斯-2。这些化合物具有吸引人的类药物性质 由此可以安全地获得相对于血浆和其它组织的高肺浓度 口服给药。一种先导化合物MCI-048被鉴定出具有很强的抗肿瘤活性， 在肺癌原位小鼠模型中的活性。进一步的模拟开发，以确定 临床前候选药物开发和研究，以更好地确定PDE 10在肺中的作用 因此，迫切需要癌症。本论文的主要目的是：1）合成一种新的 一系列舒林酸衍生物，以提高效力和选择性，2）评估PDE 10和肺 舒林酸衍生物的肿瘤细胞生长抑制活性，3）评价舒林酸衍生物的抗肿瘤活性， 舒林酸衍生物在肺癌小鼠模型中的作用，以及4）进一步确定PDE 10在 肺癌本项目的重点是开发新型抗癌药物和靶点 化学预防或治疗的验证有可能影响有以下风险的个体： 发展中的肺癌以及患有晚期恶性疾病的患者。

Abstract Preclinical, clinical and epidemiological studies provide compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic activity and significantly reduce the incidence and risk of death from multiple cancer types, including lung cancer. Unfortunately, the long-term use of NSAIDs for chemoprevention and their potential application for therapy are not recommended because of the risk of potentially fatal side-effects resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. However, numerous investigators have concluded that the pharmacological basis for their antineoplastic activity may not require COX inhibition, which suggests the feasibility of developing safer and more efficacious non-COX inhibitory derivatives for cancer by targeting the underlying mechanism. We have extensively studied the mechanism by which the NSAID, sulindac inhibits tumor cell growth and have reported that this activity results from cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition and the activation of cGMP/protein kinase G signaling to suppress oncogenic β-catenin/Tcf-transcriptional activity and the synthesis of key proteins, such as cyclin D1 and survivin that drive tumor cell proliferation and survival. Here we show that the cGMP degrading PDE isozyme, PDE10A is a critically important target of sulindac that is elevated in lung tumors and essential for lung tumor cell growth. Guided by molecular modeling using the crystal structure of PDE10, we synthesized a novel series of sulindac derivatives that potently and selectively inhibit lung tumor cell growth without inhibiting COX-1 or COX-2. These compounds have attractive drug-like properties whereby high lung concentrations relative to plasma and other tissues can be safely achieved by oral administration. A lead compound, MCI-048 was identified that displays strong antitumor activity in an orthotopic mouse model of lung cancer. Further analog development to identify a preclinical drug development candidate and studies to better define the role of PDE10 in lung cancer are therefore urgently needed. The following aims are proposed: 1) synthesize a novel series of sulindac derivatives to improve potency and selectivity, 2) evaluate PDE10 and lung tumor cell growth inhibitory activity of sulindac derivatives, 3) evaluate antitumor activity of sulindac derivatives in mouse models of lung cancer, and 4) further define the role of PDE10 in lung cancer. The focus of this project on the development of novel anticancer drugs and target validation for chemoprevention or therapy have the potential to impact individuals at risk of developing lung cancer as well as patients with advanced stage malignant disease.