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Synonyms: SCH 66336 | SCH-66336 | SCH66336 | Zokinvy®
lonafarnib is an approved drug (FDA (2020), EMA (2022))
Compound class:
Synthetic organic
Comment: Lonafarnib is an orally bioavailable molecule which inhibits farnesyl protein transferase, an enzyme that is responsible for catalysing the transfer of a 15-carbon isoprenoid group to a variety of cellular proteins including RAS [7].
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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Summary of Clinical Use  |
| Lonafarnib was evaluated as a potential anti-hepatitis therapy. Phase 3 studies for myelodysplastic syndromes (NCT00109538) and non-small cell lung cancer (NCT00050336) were terminated. Click here to link to ClinicalTrials.gov's listing of all lonafarnib trials. Lonafarnib was advanced to clinical trial as a treatment for the premature ageing disease progeria by Eiger BioPharmaceuticals (link here to Orphanet's progeria page) [3-4], and in November 2020 the FDA approved its use as the first drug for this ultra-rare disease, and for related processing-deficient progeroid laminopathies. In the clinical trials lonafarnib increased average survival time by 2.5 years. In the EU, two orphan designations have been granted that permit use of lonafarnib for hepatitis delta virus infection (2014) and Hutchinson-Gilford progeria syndrome (2018). Full EMA approval for the treatment of Hutchinson-Gilford progeria syndrome or processing-deficient progeroid laminopathies was issued in 2022. |
| Mechanism Of Action and Pharmacodynamic Effects |
| Lonafarnib is an orally bioavailable molecule which inhibits the farnesyltransferase responsible for catalysing the transfer of a 15-carbon isoprenoid group to a variety of cellular proteins including RAS [7]. Farnesyltransferase inhibition blocks the accumulation of defective, farnesylated proteins that inappropriately associate with lipid membranes. In terms of ongogenic RAS proteins, lonafarnib acts as an indirect inhibitof of RAS activity, as RAS is dependent on carboxy-terminal prenylation for attachment to its correct subcellular membrane-bound locations. Additional studies suggest that lonafarnib may also act through non-RAS mediated mechanisms. In progeria the mechanism appears to involve inhibition of prenylation of the progerin protein (mutant prelamin A), which carries the same CAAX carboxy-terminal motif as the RAS proteins- see Young et al. (2013) for further explanation of the molecular mechanism in progeria [8]. Moorthy et al. (2013) review farnesyltransferase inhibitors [6]. However, the promise of FTIs has not been bourne out in cancer clinical trials [1], perhaps due to redundancy in the system which sees geranylgeranyltransferase taking over the prenylation process, when farnesyltransferase is inhibited. |
| Clinical Trials | |||||
| Clinical Trial ID | Title | Type | Source | Comment | References |
| NCT03895528 | Lonafarnib for Patients With Hutchinson-Gilford Progeria Syndrome or Progeroid Laminopathy | Expanded Access | Eiger BioPharmaceuticals | ||
| NCT00916747 | Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria | Phase 2 Interventional | Boston Children's Hospital | 2 | |
