Discovery of Next-Generation HIF-2alpha Inhibitors for Kidney Cancer
Abstract
Most kidney tumors are clear cell Renal Cell Carcinoma (ccRCC), characterized by high-levels of hypoxia-inducible factor-2alpha (HIF-2a) protein. HIF-2a acts as the driver of ccRCC and its metastases, and blocking its function is now a clinically proven approach for treating ccRCC. The Food and Drug Administration (FDA) has approved the small molecule Belzutifan in 2021, as a first-in-class HIF-2a inhibitor for treatment of ccRCC. However, preclinical and clinical data have demonstrated that prolonged use of Belzutifan can lead to certain drug-resisting mutations in the HIF-2a protein and its partner ARNT protein, rendering Belzutifan ineffective against ccRCC. The overall objective of the proposal is to discover a new set of HIF-2a small-molecule inhibitors that cannot be compromised by any of the known resistance mutations in that protein. The proposal takes three separate strategies to identify such drug-like compounds. These strategies are (a) finding inhibitor compounds that bind to a new surface of the HIF-2a protein where resistance mutations do not occur, (b) re-designing the chemical structures of existing HIF-2a inhibitors to maintain their effectiveness despite resistance mutations, and (c) designing and testing compounds that cause HIF-2a degradation, as another approach to effectively bypass resistance mutations. As the proposal seeks to identify new compounds for future development as ccRCC therapies, its goals are well-aligned with the FY21 KCRP Focus Area Developing New Therapeutic Strategies for the Treatment of Kidney Cancer. Belzutifan represents a first-in-class HIF-2a inhibitor for ccRCC, but significant numbers of patients are expected to become resistant to it after prolonged use. The compounds that emerge from this proposal are expected to overcome resistance mutations in the HIF-2a protein, and thus will be clearly differentiated from Belzutifan. While the path to FDA drug-approval requires significantly longer time than the timeline of this proposal, and involves many additional preclinical, animal, and human clinical trial studies, reaching the proposal goals would constitute a significant breakthrough in the short term, as there are currently no drug-like compounds that can overcome the resistance mutations. Our goals and experimental approaches are highly innovative and have not been pursued by others to date. We present strong evidence in support of the feasibility of our goals based on recently published insights and findings from our laboratory. These findings include the direct visualization of the HIF-2a protein atomic structure, understanding binding modes used by various compounds including Belzutifan, and uncovering how resistance mutations render HIF-2a protein insensitive to inhibition by Belzutifan. The availability of all these key structural insights provides a powerful framework for the discovery, design, and testing of new compounds that will be effective in the face of resistance mutations. Kidney cancer accounts for 2% to 3% of all adult malignancies in the United States, and was diagnosed in over 70,000 patients in the U.S., and causing over 14,000 deaths in 2019. The most commonly diagnosed kidney cancer type is ccRCC, which accounts for over 80% of cases. Approximately 30% of ccRCC patients have metastatic disease at the time of diagnosis. Increased HIF-2a protein level and activity is the hallmark of ccRCC, and the proposal is focused on this protein as a target for drug discovery. In the military population, ccRCC is seen primarily in those over 40 years of age and within the Veteran population. The incidence of RCC for military members after age 40 is believed to be nearly six times that of the general population. Therefore, discovery of second-generation treatment options for ccRCC is likely to have an outsized benefit for the military population, while also beneficial to the general population at large.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210821
Entities
People
- Fraydoon Rastinejad
Organizations
- United States Army
- University of Oxford