Targeting RAS oncogenes is a priority for the National Cancer Institute since they are the foremost human cancer drivers. In fact, mutations in RAS contribute to approximately 30% of all cancers, including large fractions of colorectal carcinoma, lung carcinoma, and most pancreatic carcinoma. Hence, the ability to therapeutically address mutant RAS would have a significant impact on cancer mortality. The importance of the most commonly found mutant RAS, KRAS has been appreciated for decades but despite much effort, there are no FDA-approved therapies that effectively target this oncogene due to the difficulty of developing KRas inhibitors. However, an in silico conformational analysis of the GDP- vs. GTP-bound KRas structures revealed a potential ligand pocket that is only present in the GTP-bound structure. Here, we propose to use a structure-guided small molecule design strategy to develop ligands that are high affinity and selective for that GTP-bound conformational pocket. Once designed, synthesized and characterized, these ligands will serve as KRas recruiting moieties in future KRas-targeting Proteolysis Targeting Chimerae (PROTACs), a technology developed in my lab that directs specifically-targeted proteins to the ubiquitin-proteasome system for their efficacious destruction. By ultimately developing novel KRas degrading molecules, we aim to make KRas pharmaceutically vulnerable.

Public Health Relevance

While different constellations of genetic mutations give rise to the known variability among different tumor types, a few genes are highly mutated in most cancers. One such `oncogenic driver' mutation is in the gene KRas. Unfortunately, no current therapies target KRAS; however, we propose a novel strategy to eliminate KRas from tumor cells and thus block their growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA201986-02
Application #
9186518
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Knowlton, John R
Project Start
2015-12-01
Project End
2017-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520