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.

Kevan M. Shokat, a professor of cellular and molecular pharmacology at UCSF, a professor of chemistry at UC Berkeley and an investigator with the Howard Hughes Medical Institute, 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. Shokat 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.

This seminar is part of the Pharmaceutical Sciences Seminar Series/WARF Therapeutics Distinguished Lecture in Drug Discovery. To obtain the Webex link, contact Debra King at [email protected].