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

> **NIH NIH R44** · KUDA THERAPEUTICS, INC. · 2022 · $1,425,000

## Abstract

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 th...

## Key facts

- **NIH application ID:** 10598427
- **Project number:** 2R44CA217385-03A1
- **Recipient organization:** KUDA THERAPEUTICS, INC.
- **Principal Investigator:** Robert Lippert
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,425,000
- **Award type:** 2
- **Project period:** 2018-06-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598427

## Citation

> US National Institutes of Health, RePORTER application 10598427, Development of a novel dual HIF-α inhibitor and inducer of ferroptosis for kidney cancer (2R44CA217385-03A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10598427. Licensed CC0.

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