Mutations in the protein KRAS drive nearly 30% of human cancers, making it a key target for new cancer therapies. In his lecture, Prof. Kevan Shokat will present innovative strategies to target previously difficult-to-treat KRAS mutations, improve drug effectiveness, and overcome treatment resistance.
Somatic mutations in the small GTPase K-Ras drive roughly 30% of human cancers, yet the protein was long considered „undruggable“ until a covalent strategy targeting the G12C mutant revealed a binding pocket in the switch-II region, leading to the approval of sotorasib and adagrasib. These successes have shifted the central challenges in the field: extending covalent and non-covalent strategies to the more prevalent G12D and G12V mutants found in pancreatic and colorectal cancer, deepening single-agent responses, and overcoming the drug resistance that inevitably emerges with any targeted therapy.
In this lecture I will describe our efforts on each front. First, I will show that combining the pan-Ras tri-complex inhibitor daraxonrasib — whose GAP-mimetic activity accelerates GTP hydrolysis — with switch-II pocket inhibitors selective for K-Ras(G12C) or K-Ras(G12D) produces synergistic inhibition, providing a mechanistic rationale for combination regimens. Second, I will present a new covalent chemistry that installs a warhead reactive toward the aspartate of K-Ras(G12D), extending covalent targeting beyond cysteine residues and inhibiting oncogenic signaling in cancer cells.
Finally, I will place this work in the context of two broader chemical biology themes from our lab that inform how such inhibitors are designed and delivered: the discovery that IFITM proteins govern cellular uptake of chemically linked, bivalent compounds, and a binary pharmacology strategy that restricts mTOR inhibition to brain tissue. Together these findings illustrate how mechanistic combination logic, new covalent chemistries, and uptakeand tissue-informed drug design are converging to widen the therapeutic reach for new medicines.
Kevan Shokat is professor at the Department of Cellular and Molecular Pharmacology at the University of California, San Francisco, and a professor of chemistry at the University of California, Berkeley. He has been awarded the Camille & Henry Dreyfus Lectureship for his outstanding achievements in the field of chemical biology. Research in his group is dedicated to the use of chemical genetics to study and target signaling proteins, with the aim of finding new ways to treat human diseases.
Kevan Shokat (born in 1964) received his B.A. from Reed College in 1986, his PhD at UC Berkeley in 1991, and did then a post-doctoral training at Stanford University. In 1994, he began his independent career at Princeton University. He moved to the University of California, San Francisco, in 1999 where he remains today as Professor of Cellular and Molecular PharmacologyProfessor Pharmacology.
In recognition of his achievements Kevan Shokat has received numerous honors and awards, including the Stephenson Global Prize for research in pancreatic cancer, the annual Award for Scientific Discovery from the National Academy of Sciences, the Sjöberg Prize from the Swedish Academy of Sciences, and elections to the National Academy of Sciences and the National Academy of Medicine.
Introduction
- Prof. Dr. Primo Schär (Vice President for Research)
- Prof. Dr. Stefan Willitsch (Head Department of Chemistry)
Camille and Henry Dreyfus Lectures
In memory of the Dreyfus brothers, the Camille and Henry Dreyfus Foundation Inc. has established an annual Lectureship at the University of Basel. The Camille and Henry Dreyfus Lectureship brings a leading chemist from the United States to the Basel campus to deliver a series of talks and to meet with faculty and students in order to enhance the relationship between Swiss and U.S. science.