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 uptake-and tissue-informed drug design are converging to widen the therapeutic reach for new medicines.

Camille & Henry Dreyfus Lectureship
In memory of the Dreyfus brothers, the Camille and Henry Dreyfus Foundation Inc. has established the Camille & Henry Dreyfus Lectureship at the University of Basel. The annual 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.