lonafarnib   Click here for help

GtoPdb Ligand ID: 8024

Synonyms: SCH 66336 | SCH-66336 | SCH66336 | Zokinvy®
Approved drug PDB Ligand
lonafarnib is an approved drug (FDA (2020), ENA (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].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 5
Topological polar surface area 79.53
Molecular weight 636.05
XLogP 4.45
No. Lipinski's rules broken 0
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Canonical SMILES Clc1cc(Br)c2c(c1)CCc1c(C2C2CCN(CC2)C(=O)CC2CCN(CC2)C(=O)N)ncc(c1)Br
Isomeric SMILES Clc1cc(Br)c2c(c1)CCc1c([C@@H]2C2CCN(CC2)C(=O)CC2CCN(CC2)C(=O)N)ncc(c1)Br
InChI InChI=1S/C27H31Br2ClN4O2/c28-20-12-19-2-1-18-13-21(30)14-22(29)24(18)25(26(19)32-15-20)17-5-9-33(10-6-17)23(35)11-16-3-7-34(8-4-16)27(31)36/h12-17,25H,1-11H2,(H2,31,36)/t25-/m1/s1
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Summary of Clinical Use Click here for help
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 Click here for help
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