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

• 批准号: 10598427
• 负责人: Robert Lippert
• 金额: $ 142.5万
• 依托单位: KUDA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 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/10598427
• 关键词: Advanced Development; Animals; Apoptosis; Autophagocytosis; Binding; Cancer Biology; Cancer Model; Caspase Inhibitor; Cell Death; Cells; Cessation of life; Characteristics; Chemotherapy and/or radiation; Clear cell renal cell carcinoma; Clinic; Clinical Management; Clinical Trials; Combined Modality Therapy; Deferoxamine; Development; Disease; Dose; Dose-Limiting; Drug Industry; Drug resistance; Elements; Formulation; Fund Raising; 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 Chelating Agents; 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; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Polymorph; Population; 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; base; cancer cell; candidate marker; checkpoint inhibition; clinical development; commercialization; 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; therapeutic target; treatment strategy; tumor; tumor growth; tumor xenograft

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 肾癌是美国人口中第八大常见癌症，其中透明细胞肾细胞癌 (ccRCC) 是最常见的亚型。 ccRCC 对标准化疗和放疗非常难治，并且 晚期或转移性肿瘤患者的 5 年生存率仅为 14%。 ccRCC 通常启动 通过 von Hippel Lindau (VHL) 肿瘤抑制因子的失活，导致 缺氧诱导因子 HIF-1α 和 HIF-2α。 HIF 是 ccRCC 有希望的治疗靶点，因为 已知它们参与疾病的发病机制，并且它们在正常灌注良好的细胞中缺乏表达 组织。此外，细胞内脂质的积累是 ccRCC 的一个决定性特征，这使得 它们特别容易受到与铁依赖性脂质过氧化或铁死亡相关的细胞死亡的影响。通过 Kuda Therapeutics 在谓词 SBIR 一期项目中努力优化选择性 HIF-2α 抑制剂 鉴定了一系列新化合物，包括先导 KD061，可降低 HIF-1α 和 HIF-2α，并诱导 通过与新的分子靶标铁硫簇组装 2 (ISCA2) 结合，在体外和体内发生铁死亡。 ISCA2 抑制会触发铁饥饿反应，从而抑制铁反应元件 (IRE) 依赖性 HIF-2α 的翻译，并引发铁过载，从而导致铁死亡。引人注目的是，pVHL 缺陷 与具有以下特征的细胞相比，ccRCC 细胞的 ISCA2 水平降低，并且对 ISCA2 抑制更敏感 pVHL 重建，表明选择性靶向 pVHL 缺陷的 ccRCC 细胞的治疗窗口 对正常、pVHL 丰富的组织具有最小的毒性。在小鼠中，KD061 治疗显着介导 >60% 通过口服抑制 RENCA 同基因异种移植肿瘤生长，且未检测到毒性 在治疗剂量下，验证了这种治疗 ccRCC 的新方法。本次 SBIR 的目标 II期项目旨在进一步表征Kuda双重HIF-α抑制剂和铁死亡的功效和安全性 感应引线 KD061。这项工作将推动其向研究性新药 (IND) 备案和 针对 ccRCC 患者初始治疗的首次人体研究。我们的首要目标是优化KD061药物 物质、配方和合成。在这里我们将进行盐筛选、多晶型筛选和配方 研究以确定 KD061 在体内口服给药的最佳形式，然后扩大合成规模以提高功效和 毒理学研究。我们的第二个目标是表征 KD061 作为单一药物的体内抗肿瘤功效 在多种 ccRCC 小鼠模型中，并与舒尼替尼或 PD-1 免疫检查点抑制联合使用 RENCA 同基因肾癌模型。我们的第三个目标是确定 KD061 在啮齿动物体内的毒理学 和非啮齿类动物，通过执行行业标准非 GLP 和 GLP 研究来确定起始剂量 以及人体临床试验的剂量限制毒性来源。在第二阶段完成时，我们将生产 优化KD061原料药，并表征其有效性和安全性，显着推动KD061走向 IND 申请和首次人体试验可以开始改变 ccRCC 患者的生活。