Novel and Selective AMPK Activator for the Treatment of Hepatocellular Carcinoma

项目总结/摘要 肝癌，主要是肝细胞癌（HCC），每年约有662，000人死亡，是世界上最严重的肝癌。 癌症是全球第三大死因。1975年至2000年， 在美国，原发性肝癌的死亡率比其他任何癌症的死亡率增长都要快。 肿瘤类型在监测、流行病学调查中，1年和3年生存率分别为36%和17 1998年至2000年的最终结果（SEER）登记。 HCC可通过侵袭性手术、肝移植、放射、化疗栓塞或化疗来治疗。 只有一种药物（Nexavar/索拉非尼）被批准用于HCC，这将生命延长了4个月。的 引入新的和有效的治疗选择对于有效管理这种疾病是至关重要的， 特别是在肿瘤已经扩散到继发部位的情况下。 NovaTarg已经建立了一种新的HCC治疗方法，其中双胍被设计为利用 转运蛋白（OCT 1和OCT 3）在肝细胞上表达。这些双胍被HCC选择性地摄取 在细胞中，它们激活AMPK并调节细胞生长和能量利用。众所周知， LKB 1-AMPK通路在肿瘤抑制中起重要作用，抑制细胞增殖和蛋白质合成。 通过调节p53、mTOR、p27和细胞周期蛋白D1的作用来合成。二甲双胍，一种双胍， AMPK已被证明可以预防糖尿病患者发生HCC，并显示出抗肿瘤活性 在体外和体内肿瘤模型中。重要的是，二甲双胍与化疗、放疗 并且对癌症干细胞有活性。NovaTarg正在提高双胍的效力并将其靶向肝脏 用于治疗HCC的细胞。 NovaTarg双胍是二甲双胍的衍生物，其更有效，转运蛋白特异性更强， 肝癌细胞例如，一种早期的先导化合物NT 1014可有效激活肝脏中的AMPK（OCT 1）。 细胞，与二甲双胍相比，抑制Huh 7细胞生长的效力高约12倍，是一种有前途的 NovaTarg将优化先导化合物，以在该第一阶段项目中产生候选药物。使用详细 SAR分析为下一代化合物的设计提供信息，我们将在12个月内准备新的 这些分子既能将所需的药理学特征传递给HCC细胞，也能在HCC细胞中构建。 药物分子所需的物理化学性质。符合我们选择标准的化合物将 在HCC的小鼠异种移植模型中进行药代动力学分析和体内评价， 确定一种候选药物，我们将在2期申请中进行药物开发。值得 注意到双胍类药物，如二甲双胍，属于已知的药物类别， 分子特性和安全性。

Project Summary/Abstract Liver cancer, primarily hepatocellular carcinoma (HCC), accounts for ~662,000 deaths each year and is the third leading cause of death from cancer worldwide. The age-adjusted incidence of HCC tripled between 1975 and 2005 in the US, and primary liver cancer mortality rates have increased faster than mortality for any other tumor type. One- and 3-year survival rates were 36% and 17%, respectively, in the Surveillance, Epidemiology and End Results (SEER) registries from 1998 to 2000. HCC is treated by aggressive surgery, liver transplantation, radiation, chemoembolization or chemotherapy. Only one drug (Nexavar/sorafenib) is approved for HCC and this extends life by a modest 4 months. The introduction of new and efficacious therapeutic options is critical for effective management of this disease, particularly in cases where tumor has spread to secondary sites. NovaTarg has established a novel approach to HCC treatment in which biguanides are designed to utilize transporters (OCT1 and OCT3) expressed on hepatocytes. These biguanides are selectively taken up by HCC cells where they activate AMPK and regulate cell growth and energy utilization. It is well established that the LKB1-AMPK pathway plays an important role in tumor suppression; inhibiting both cell proliferation and protein synthesis by regulating the actions of p53, mTOR, p27 and cyclin D1. Metformin, a biguanide known to activate AMPK, has been shown to prevent development of HCC in diabetes patients and to display antitumor activity in vitro and in vivo in tumor models. Importantly, metformin is synergistic with chemotherapy, radiation therapy and is active against cancer stem cells. NovaTarg is improving biguanide potency and targeting them to liver cells for the treatment of HCC. NovaTarg biguanides are derivatives of metformin which are more potent, transporter specific and focused on liver cancer cells. For example an early lead compound, NT1014, potently activates AMPK in liver (OCT1) cells, is ~12x more potent at inhibiting growth of Huh7 cells as compared with metformin and is a promising lead compound that NovaTarg is will optimize to create a drug candidate in this Phase 1 project. Using detailed SAR analysis to inform the design of next generation compounds we will, over a 12 month period, prepare new molecules that both deliver the desired pharmacological profile to HCC cells, as well as building in the physicochemical properties required in a drug molecule. Compounds that meet our selection criteria will be subjected to pharmacokinetic analysis and in vivo evaluation in mouse xenograft models of HCC in order to identify a drug candidate that we will be progressed to drug development in a Phase 2 application. It is worth noting that biguanides, such as metformin, fall into a known drug class which has demonstrated good drug molecule properties and safety in human subjects.