A new small molecule drug helps to bind the naturally occurring cellular chaperone cyclophilin A (CYPA) to the active state of the cancer-causing mutant KRAS^G12C, disrupting oncogenic signaling and tumor growth in several models of human cancer. The approach could be used to target additional oncogenic KRAS mutants as well as other cancer drivers. Small-molecule drugs inhibit a target protein's function by binding to the pockets on their surfaces. Proteins that lack these pockets are often considered undruggable. KRAS is a small guanosine triphosphatase (GTPase). Its active state regulates cell growth and proliferation. Mutations of KRAS are prevalent in several cancers and are among the most common oncogenes. But given its relatively flat surface with no obvious binding pockets, it was long considered undruggable. Recently, inhibitors that selectively target the inactive state of the KRAS^G12C variant have shown some clinical promise. However, traditional small-molecule drugs that target the active state of the protein have been elusive, suggesting the need for innovative approaches to KRAS inhibition. To address this need, Christopher Schulze and colleagues designed a natural product-inspired small molecule that indirectly targets the active state of KRAS^G12C. Schulze et al. created a compound (RMC-4998) that binds to the abundant, naturally occurring compound CYPA – a type of cellular chaperone that assists in controlling proteostasis. When combined, the complex selectively targets active KRAS^G12C. The resulting CYPA:drug: KRAS^G12C tricomplex was found to inhibit oncogenic signaling and led to tumor regressions in several human cancer models. "With the seemingly untouchable active states of KRAS^G12C conquered, it will be interesting to explore whether this approach can be applied to other KRAS mutants, small GTPases, trimeric G proteins, and even other classes of 'undruggable' targets," writes Jun Liu in a related Perspective.