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))
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
SMILES / InChI / InChIKey
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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]