Targeting farnesyltransferase for cancer therapy and beyond.

Farnesyltransferase (FTase) mediates Ras prenylation, a crucial activation step. Historically, farnesyltransferase inhibitors (FTIs) failed in Ras-driven cancers because of geranylgeranyltransferase I (GGTase I)-mediated alternative prenylation of Ras. Recent advances have revitalized next-generation FTIs, developed via structure-guided design, phenotypic screening, or computational approaches, offering improved selectivity, dual FTase/GGTase I targeting, or enhanced peptidomimetic affinity to overcome resistance. Combinations with targeted agents or immunotherapies exert synergistic antitumor effects. FTIs are also explored for neurodegenerative, infectious, and viral diseases. In this review, we highlight advances in FTIs, their combination strategies and cross-disease potential, justifying why modern FTI approaches succeed where earlier ones faltered.