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(NSAIDs)具有抗肿瘤活性，显著 降低多种癌症类型的发病率和死亡风险，包括肺癌。 不幸的是，长期使用非类固醇抗炎药进行化学预防及其潜在应用 因为有潜在致命副作用的风险，所以不推荐进行治疗 从环氧合酶(COX)的抑制和生理意义的抑制 前列腺素。然而，许多调查人员得出结论，这种药理作用 其抗肿瘤活性的基础可能不需要COX抑制，这表明 通过以下途径开发更安全、更有效的非COX抑制癌症衍生物的可行性 瞄准潜在的机制。我们已经广泛地研究了 非甾体抗炎药，舒林酸可抑制肿瘤细胞生长，并已报道这种活性是由环状 鸟苷单磷酸二酯酶(CGMP PDE)的抑制和激活 CGMP/蛋白激酶G信号通路抑制癌基因β-连环蛋白/Tcf转录活性 以及驱动肿瘤细胞的关键蛋白的合成，如细胞周期蛋白D1和Survivin 扩散和生存。我们证明了cGMP降解PDE同工酶PDE10A是一种 舒林酸在肺癌中升高并对肺癌至关重要的重要靶点 细胞生长。在利用PDE10晶体结构进行分子模拟的指导下，我们合成了 一系列新的有效和选择性抑制肺肿瘤细胞生长的舒林酸衍生物 而不抑制COX-1或COX-2。这些化合物具有诱人的类药物特性。 由此可以安全地实现相对于血浆和其他组织的高肺浓度 口服给药。鉴定出一种具有强抗肿瘤活性的先导化合物MCI-048 肺癌原位小鼠模型的活动性。进一步的模拟开发，以确定 临床前药物开发候选者和更好地确定PDE10在肺中的作用的研究 因此，人们迫切需要癌症。提出了以下目标：1)合成一部小说 舒林酸系列衍生物以提高效力和选择性，2)评估PDE10和肺 舒林酸衍生物对肿瘤细胞生长的抑制作用，3)评价舒林酸衍生物的抗肿瘤活性 舒林酸衍生物在小鼠肺癌模型中的作用，以及4)进一步确定PDE10在 肺癌。本项目的重点是新型抗癌药物的开发和靶点 对化学预防或治疗的验证有可能影响有风险的人 发展中的肺癌以及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.