darlifarnib

Darlifarnib is an investigational, orally bioavailable, potent next-generation **farnesyl transferase inhibitor (FTI)** designed to potentially improve upon earlier FTI drug candidates like tipifarnib. Upon oral administration, darlifarnib targets, binds to, and inhibits the enzyme farnesyl transferase, thereby preventing the farnesylation of proteins. This mechanism prevents the activation of Ras oncogenes, inhibits Ras-dependent signaling, and blocks the proliferation of tumor cells in which Ras is overexpressed or mutated. Darlifarnib demonstrates enhanced potency and selectivity compared to tipifarnib, with improved pharmacokinetics optimized for combination drug development. The FTI mechanism addresses **innate and adaptive resistance pathways** common to targeted oncology therapies by blocking hyperactivated mTORC1 signaling in tumor endothelial cells and squamous tumor cells. Preclinical and early clinical data support darlifarnib's potential to enhance the clinical benefit of **PI3Kα inhibitors, KRAS inhibitors, and tyrosine kinase inhibitors**. The drug is being developed by **Kura Oncology** for treatment of various solid tumors, with particular focus on renal cell carcinoma and HRAS-mutant tumors. Darlifarnib exhibits robust on-target activity in HRAS-mutant solid tumors and demonstrates a manageable safety profile across multiple dose levels (3-10 mg/day). In combination with cabozantinib, darlifarnib achieved a 50% objective response rate and 80% disease control rate in renal cell carcinoma patients, including those previously exposed to cabozantinib.

Other names

Compound (S)-058