The MAPK pathway is critical in regulating aspects of cell cycle control, including proliferation, differentiation and survival. Pathway mutations can lead to unregulated cellular division and are therefore responsible for driving many blood and solid cancers in humans. Over 30% of all human cancers are driven by RAS genes, of which 85% are the result of KRAS mutations. This has led to KRAS being considered a “holy grail” of cancer therapy. Targeting KRAS via an inhibition approach has, however, been challenging, as it lacks traditionally druggable small molecule binding sites. Although advances have been made in recent years, the majority of disclosed therapies to date target single KRAS alleles. In this seminar, we will discuss two PROTAC projects targeting proteins within the MAPK pathway, culminating in the discovery of a pan-KRAS bifunctional degrader, ACBI3, and sharing several important learnings we made along the way. Popow, J. et. al. Science, 2024, 385, 1338