Named Grant:

The Feldberg Family Project Grant

About the Investigator:

Dr. Nir London completed his PhD in computational structural biology at the Hebrew University of Jerusalem and post-doctoral fellowship at UCSF. Dr. London joined the Weizmann Institute of Science in 2015, where his lab is focused on covalent chemical biology and is developing new technologies to discover and functionalize covalently acting compounds. His honors include the Alon fellowship, the 2021 EFMC award for young medicinal chemist in academia and the 2021 ISCB award for young chemical biologist.

About the Research:

Cell growth and division are tightly controlled by a complex network of proteins that regulate these processes within and outside of cells. Disruptions or mutations in these proteins can lead to uncontrolled cell growth, resulting in cancer. Among the most significant oncogenic proteins is KRAS, where mutations keeping it in a continuously active state are frequently found in various cancers. These mutations are particularly prominent in pancreatic cancer. Developing molecules that can bind to and inhibit these active KRAS mutants are therefore a crucial goal for treating pancreatic and many other cancers.

Dr. London’s laboratory specializes in the development of covalent inhibitors, which are a type of molecule that binds irreversibly to a target protein. This project seeks to develop covalent inhibitors for KRAS G12D, the most common KRAS mutant in cancer. A major breakthrough recently occurred with the development of effective covalent inhibitors for G12C – a different, less abundant mutant. Prior to this, KRAS had long been considered “undruggable” due to its small size and other factors. Now, based on the structure of these molecules and using computational tools for inhibitor design developed by the lab, Dr. London will design, synthesize and test molecules with chemical groups that will react specifically with the G12D mutant. His team will select the best binders discovered in their initial experiments and test whether they inhibit KRAS G12D in cells and in biological experiments. The molecules developed will contribute the study of KRAS G12D biology and form a basis for the develop of potent drugs targeted against the G12D mutation. This research offers new hope for more efficacious and less toxic treatments urgently needed for treating pancreatic and other KRAS G12 cancers.