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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.

摘要