Development of a novel dual HIF-α inhibitor and inducer of ferroptosis for kidney cancer

开发一种新型双重 HIF-α 抑制剂和肾癌铁死亡诱导剂

基本信息

批准号：
10708992
负责人：
Robert Lippert
金额：
$ 62.5万
依托单位：
KUDA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10708992
关键词：
Advanced Development Angiogenesis Inhibitors Animals Apoptosis Autophagocytosis Binding Cancer Biology Cancer Model Caspase Inhibitor Cell Death Cell Death Induction Cells Cessation of life Characteristics Chemotherapy and/or radiation Clear cell renal cell carcinoma Clinic Clinical Management Clinical Trials Combined Modality Therapy Cytoprotection Deferoxamine Development Disease Dose Dose Limiting Drug Industry Drug resistance Elements Formulation Funding Future Genitourinary system Goals Grant Human Hypoxia Inducible Factor Immune checkpoint inhibitor Immunooncology In Vitro Industry Standard Inherited International Intracellular Accumulation of Lipids Investigational Drugs Investments Iron Iron Chelation Iron Overload Lead Lipid Peroxidation Malignant Epithelial Cell Malignant Neoplasms Mediating Medical Oncologist Molecular Target Mus Necrosis Neoplasm Metastasis Oral Oral Administration Pathogenesis Patient-Focused Outcomes Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Phase Play Polymorph Population Predisposition Production Property Proteins Refractory Renal carcinoma Rodent Role Safety Series Small Business Innovation Research Grant Sodium Chloride Solid Neoplasm Solubility Source Specialist Starvation Structure-Activity Relationship Sulfur Survival Rate Therapeutic Tissues Toxic effect Toxicology Translational Repression Translations Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Von Hippel-Lindau Syndrome Work Xenograft procedure candidate marker carcinogenesis checkpoint inhibition clinical development commercialization constitutive expression cytotoxic drug development experience first-in-human improved in vivo inhibitor innovation manufacturability mouse model next generation novel novel strategies novel therapeutic intervention programmed cell death protein 1 reconstitution response scale up screening small molecule synergism therapeutic target tumor tumor growth tumor xenograft

项目摘要

Abstract Kidney cancer is the 8th most common cancer in the US population, of which clear cell renal cell carcinoma (ccRCC) is the most common subtype. ccRCC is highly refractory to standard chemotherapy and radiation, and patients with advanced or metastatic tumors have a 5-year survival rate of just 14%. ccRCC is typically initiated by inactivation of the von Hippel Lindau (VHL) tumor suppressor, which results in the constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. The HIFs are promising therapeutic targets for ccRCC due to their known involvement in the pathogenesis of the disease, and their lack of expression in normal well-perfused tissue. Additionally, the intracellular accumulation of lipids, which is a defining characteristic of ccRCC, renders them uniquely susceptible to cell death associated with iron-dependent lipid peroxidation or ferroptosis. Through efforts to optimize selective HIF-2α inhibitors in the predicate SBIR Phase I project, Kuda Therapeutics has identified a series of novel compounds, including lead KD061, that decrease both HIF-1α and HIF-2α, and induce ferroptosis in vitro and in vivo, by binding to the novel molecular target, Iron Sulfur Cluster Assembly 2 (ISCA2). ISCA2 inhibition triggers the iron starvation response, which inhibits iron-responsive element (IRE)-dependent translation of HIF-2α, and triggers iron overload, which results in ferroptotic death. Strikingly, pVHL-deficient ccRCC cells have decreased ISCA2 levels and are more sensitive to ISCA2 inhibition compared to cells with pVHL reconstitution, suggesting a therapeutic window for the selective targeting of pVHL-deficient ccRCC cells with minimal toxicity to normal, pVHL-proficient tissue. In mice, KD061 treatment mediates significant >60% inhibition of RENCA syngeneic xenograft tumor growth through oral administration with no detectable toxicities at the therapeutic dose, validating this novel approach for the treatment of ccRCC. The objective of this SBIR Phase II project is to further characterize the efficacy and safety of Kuda’s dual HIF-α inhibitor and ferroptosis inducer lead KD061. This work will advance its development towards Investigational New Drug (IND) filing and first-in-human studies for the initial treatment of patients with ccRCC. Our first aim is to optimize KD061 drug substance, formulation and synthesis. Here we will perform salt screening, polymorph screening and formulation studies to identify the optimal form of KD061 for oral delivery in vivo, then scale-up synthesis for efficacy and toxicology studies. Our second aim is to characterize the in vivo anti-tumor efficacy of KD061 as a single agent in multiple mouse models of ccRCC, and in combination with sunitinib or PD-1 immune checkpoint inhibition in the RENCA syngeneic kidney cancer model. Our third aim is to determine in vivo toxicology of KD061 in a rodent and non-rodent species by performing industry standard non-GLP and GLP studies to identify the starting doses and sources of dose limiting toxicities for human clinical trials. At Phase II completion, we will have produced the optimal KD061 drug substance, and characterized its efficacy and safety, significantly advancing KD061 towards IND filing and first-in-human trials where it can begin to make a difference in the lives of patients with ccRCC.

抽象的肾癌是美国人群中第八大癌症，其中清晰的细胞肾细胞癌（CCRCC）是最常见的亚型。 CCRCC对标准化疗和放射线高度难治性，并且患有晚期或转移性肿瘤的患者的生存率仅为14％。通常启动CCRCC 通过失活的von hippel lindau（VHL）抑制剂，这导致了构成激活缺氧诱导因子HIF-1α和HIF-2α。 HIF由于他们已知参与该疾病的发病机理，并且在正常良好的正常中缺乏表达组织。另外，脂质的细胞内积累，这是CCRCC的定义特征它们独特地易受与铁依赖性脂质过氧化或铁铁作用相关的细胞死亡。通过在谓词SBIR I期项目中优化选择性HIF-2α抑制剂的努力，Kuda Therapeutics具有确定了一系列新化合物，包括铅KD061，可降低HIF-1α和HIF-2α，并诱导通过与新型分子靶靶标，铁硫簇组装2（ISCA2）结合，体外和体内的铁凋亡。 ISCA2抑制作用会触发铁饥饿反应，该反应抑制了铁反应元件（IRE）依赖性 HIF-2α的翻译和触发铁超负荷，从而导致铁毒性死亡。引人注目的是，pvhl difient CCRCC细胞的ISCA2水平降低，并且与具有ISCA2抑制更敏感 PVHL重建，建议选择性靶向PVHL缺乏CCRCC细胞的治疗窗口对正常的PVHL功能组织的毒性最小。在小鼠中，KD061治疗介导了显着> 60％通过口服给药抑制Renca syngeneic异种移植肿瘤的生长，没有可检测的毒性在治疗剂量下，验证了这种新颖的CCRCC治疗方法。这个Sbir的目的第二阶段项目是为了进一步表征KUDA双HIF-α抑制剂和铁凋亡的效率和安全性诱导者铅KD061。这项工作将使其发展朝着调查新药（IND）提交和首先是人类的研究，用于对CCRCC患者的初始治疗。我们的第一个目的是优化KD061药物物质，配方和合成。在这里，我们将进行盐筛选，多晶型筛查和配方研究以确定用于体内口服递送的KD061的最佳形式，然后扩展合成以提高效率和毒理学研究。我们的第二个目的是表征KD061的体内抗肿瘤效率在多个CCRCC的小鼠模型中，并与Sunitinib或PD-1免疫切口点结合 Renca Syngeneic肾癌模型。我们的第三个目的是确定啮齿动物中KD061的体内毒理学通过执行行业标准非GLP和GLP研究来识别起始剂量和剂量限制人类临床试验的毒性的来源。在第二阶段完成时，我们将生产最佳的KD061药物，并表征了其有效性和安全性，可显着前进KD061 IND提交和人类的第一次试验可以开始改变CCRCC患者的生活。