Discovery of novel inhibitors for human farnesyltransferase (hFTase) via structure-based virtual screening

In this study, 22 novel hFTase inhibitors containing 18 scaffolds were identified with IC₅₀ values ranging from 0.0119 to 13.35 μM by structure-based virtual screening, and compounds 2, 7, 9, 10, 14 and 15 showed moderate antiproliferative activity against MCF-7 cells. In particular, compound 2 was the most promising lead compound with nanomolar activity against FTase and antiproliferative activity in the low micromolar range. Possible binding modes of the hit compounds were explored and their structure-activity relationships (SAR) were elucidated by molecular docking simulation. The hit compounds discovered in this work will provide novel scaffolds for further hit-to-lead optimization and lay the foundation for further development of therapeutic candidates for cancer treatments.