Therapeutic Targeting of Mutant VHL Through Structure-Based Drug Design
Abstract
At present, surgery remains the preferred treatment option for localized and accessible renal cell carcinomas. In more advanced cases certain targeted therapies can be used, aimed mostly at preventing formation of new blood vessels needed by the tumor for supplying nutrients to support its growth. The majority of renal cell carcinomas are driven by a mutation in VHL, an important tumor suppressor gene. The VHL gene encodes the protein pVHL, that, in healthy cells, eliminates the protein HIF. The cancer-promoting HIF protein, in turn, is responsible for producing the factors that promote blood vessel formation, tumor progression, and metastasis. In order to degrade HIF, the pVHL protein must adopt a specific 3D structure. We recently recognized that many of the VHL mutations seen in kidney cancers map to the interior of this 3D structure and destabilize it. Thus, mutant pVHL is produced in cells, but it does not adopt the 3D structure that is needed for it to degrade HIF. Our hypothesis is that if we can find drug-like chemical matter that binds to the active pVHL structure and stabilizes it, these will induce mutant pVHL to adopt the 3D structure of wild-type pVHL. By restoring its active structure, mutant pVHL would now degrade HIF, and disable all of HIF’s many cancer-promoting activities. If successful, these new chemical entities can be used to test whether restoring the activity of mutant pVHL is indeed a viable therapeutic strategy and can even serve as starting points for developing new drugs. To date, there have been no studies reporting efforts to find chemical entities that re-activate mutant pVHL: Most studies focus on finding direct inhibitors of cancer-promoting factors (like HIF), rather than activators that correct mutations in tumor suppressors. Thus, our study is innovative because it seeks to address the real underlying molecular problem in these cancer cells, rather than simply target the downstream consequences of the problem. In order to find appropriate chemical entities, we will take advantage of cutting-edge computational methods for screening billions of potential re-activators and prioritizing a manageable number for testing. We will synthesize the top-scoring compounds from our computational screen and evaluate their effect on cancer cells that harbor mutant pVHL.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010844
Entities
People
- John Karanicolas
Organizations
- United States Army