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

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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.