Pharmaceutical Sciences Seminar Series/WARF Therapeutics Distinguished Lecture in Drug Discovery
Kevan M. Shokat, PhD
- Professor, Department of Cellular and Molecular Pharmacology, UCSF
- Professor, Department of Chemistry, UC Berkeley
- Investigator, Howard Hughes Medical Institute
New Strategies to Drug Challenging Targets by Exploiting Covalent Targeting, Beyond Rule of 5 Bitopic Ligands and Binary Pharmacology
The GTP-ase K-Ras represents the most frequently altered oncogene in cancer patients. Directly targeting K-Ras is difficult due to its picomolar affinity for GTP/GDP and the absence of easily identifiable allosteric sites.
I will describe the discovery of small molecules that covalently bind to a common oncogenic mutant, K-RasG12C. These compounds have served as a blueprint for the development of multiple K-RasG12C drugs currently undergoing clinical investigation.
Many drug discovery efforts are hampered by the size limit of cell permeable ligands. I will discuss an unusually large (>1700Da) bitopic ligand termed Rapa-Link which inhibits all drug resistant forms of the nutrient sensor kinase, mTOR. The particular physicochemical properties of this molecule can be exploited to overcome a common challenge in drug discovery termed on target/off tissue toxicity by leveraging a new binary pharmacology platform.
Hosted by Professor Chuck Lauhon