Novel and Selective AMPK Activator for the Treatment of Hepatocellular Carcinoma

用于治疗肝细胞癌的新型选择性 AMPK 激活剂

基本信息

批准号：
8644551
负责人：
Ken W Batchelor
金额：
$ 22.5万
依托单位：
NOVATARG, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-23 至 2016-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644551
关键词：
Accounting Adverse effects Affinity Age Animal Model Area BAY 54-9085 Biguanides Cancer Etiology Cause of Death Cell Proliferation Cell model Cells Cessation of life Chemistry Chemoembolization Clinical Research Cyclin D1 Development Diabetes Mellitus Disease Disease Management Dose Drug Formulations Drug Kinetics Effectiveness Evaluation Excretory function Family Goals Growth Hepatocyte Incidence Insulin Kidney Lactic Acidosis Lead Life Liver Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Measures Medical Medical Surveillance Metabolic Clearance Rate Metabolism Metformin Modeling Mus Nexavar Non-Insulin-Dependent Diabetes Mellitus Odds Ratio Operative Surgical Procedures Organ POU2F1 gene POU2F2 gene Pathway interactions Patients Pharmaceutical Preparations Phase Phosphotransferases Play Preclinical Testing Primary carcinoma of the liver cells Procedures Property Protein Biosynthesis Radiation Radiation therapy Rattus Registries Reporting Resected Risk Role STK11 gene Safety Secondary to Selection Criteria Series Site Sulfonylurea Compounds Survival Rate System Therapeutic Tumor Suppression Work Xenograft Model Xenograft procedure base cancer cell cancer stem cell cancer therapy cell growth chemotherapy commercialization design diabetic patient drug candidate drug development effective therapy falls human FRAP1 protein human subject improved in vitro activity in vivo innovation liver transplantation meetings mortality mouse model neoplastic cell next generation novel novel strategies novel therapeutic intervention preclinical study prevent protective effect public health relevance tumor tumor growth

项目摘要

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.

项目摘要/摘要肝癌，主要是肝细胞癌（HCC），每年造成约662,000人死亡，是全球癌症的第三大死亡原因。 1975年之间，HCC年龄调整的HCC发生率增加了两倍在美国，2005年以及原发性肝癌死亡率的增长速度快于死亡率的速度快肿瘤类型。在监测中，一年和3年的生存率分别为36％和17％从1998年到2000年的最终结果（SEER）注册表。 HCC通过侵略性手术，肝移植，放射线，化学栓塞或化学疗法来治疗。仅批准一种药物（Nexavar/Sorafenib）用于HCC，这将寿命延长了4个月。这引入新的有效的治疗选择对于有效管理该疾病至关重要，特别是在肿瘤扩散到次要部位的情况下。 Novatarg已经建立了一种新型的HCC治疗方法，其中Biguanides设计用于利用转运蛋白（OCT1和OCT3）在肝细胞上表达。这些Biguanides由HCC选择性地采用它们激活AMPK并调节细胞生长和能量利用。众所周知， LKB1-AMPK途径在肿瘤抑制中起重要作用。抑制细胞增殖和蛋白质通过调节p53，mTOR，p27和细胞周期蛋白D1的作用来合成。二甲双胍，已知激活的Biguanide AMPK已被证明可以防止糖尿病患者的HCC发展并显示抗肿瘤活性体外和体内肿瘤模型。重要的是，二甲双胍与化学疗法，放射治疗是协同作用并且对癌症干细胞有效。 Novatarg正在改善Biguanide的效力，并将其瞄准肝脏用于治疗HCC的细胞。 novatarg biguanides是二甲双胍的衍生物，更有效，特定于转运蛋白，专注于肝癌细胞。例如，早期铅化合物NT1014有效激活肝脏中的AMPK（OCT1）与二甲双胍相比 Novatarg将在此第1阶段项目中创建候选药物的铅大院。使用详细 SAR分析以告知下一代化合物的设计，我们将在12个月内准备新既将所需的药理学特征都传递给HCC细胞的分子，又要在药物分子中需要的物理化学特性。符合我们选择标准的化合物将是进行HCC小鼠异种移植模型中的药代动力学分析和体内评估，以便确定一个候选药物，我们将在第二阶段的应用中发展为药物开发。值得注意到诸如二甲双胍之类的biguanides属于已知的药物类别，该类别表现出了很好的药物人类受试者的分子特性和安全性。