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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Ligand Activity Visualisation Charts

These 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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View interactive charts of activity data across species

lonafarnib is commercially available from our sponsors

2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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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
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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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
InChI Key DHMTURDWPRKSOA-RUZDIDTESA-N
References
1. Downward J. (2003)
Targeting RAS signalling pathways in cancer therapy.
Nat Rev Cancer, 3 (1): 11-22. [PMID:12509763]
2. Gordon LB, Kleinman ME, Massaro J, D'Agostino Sr RB, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A et al.. (2016)
Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.
Circulation, 134 (2): 114-25. [PMID:27400896]
3. Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD et al.. (2012)
Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.
Proc Natl Acad Sci USA, 109 (41): 16666-71. [PMID:23012407]
4. Gordon LB, Shappell H, Massaro J, D'Agostino Sr RB, Brazier J, Campbell SE, Kleinman ME, Kieran MW. (2018)
Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome.
JAMA, 319 (16): 1687-1695. [PMID:29710166]
5. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L, Prioli N et al.. (1998)
Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice.
Cancer Res, 58 (21): 4947-56. [PMID:9810004]
6. Moorthy NS, Sousa SF, Ramos MJ, Fernandes PA. (2013)
Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis.
Curr Med Chem, 20 (38): 4888-923. [PMID:24059235]
7. Taveras AG, Kirschmeier P, Baum CM. (2003)
Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations.
Curr Top Med Chem, 3 (10): 1103-14. [PMID:12769711]
8. Young SG, Yang SH, Davies BS, Jung HJ, Fong LG. (2013)
Targeting protein prenylation in progeria.
Sci Transl Med, 5 (171): 171ps3. [PMID:23390246]