Lonafarnib
Identification
- Summary
Lonafarnib is a potent farnesyl transferase inhibitor used to reduce mortality associated with Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid laminopathies.
- Brand Names
- Zokinvy
- Generic Name
- Lonafarnib
- DrugBank Accession Number
- DB06448
- Background
Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in adverse symptoms associated with premature ageing: skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive; HGPS is uniformly fatal.1,2,3,4,5 Mechanistically, HGPS is underpinned by a single heterozygous C-to-T mutation at position 1824 of the LMNA gene, which results in the accumulation of an aberrant farnesylated form of lamin A called progerin in the inner nuclear membrane.1,4 Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), which reduces the farnesylation of numerous cellular proteins, including progerin; as progerin farnesylation is important for localization to the nuclear membrane, lonafarnib inhibits progerin accumulation and improves symptoms in HGPS patients.1,9,10,13
Merck originally developed Lonafarnib and subsequently licensed it to Eiger Biopharmaceuticals Inc., which currently markets it under the trademark ZOKINVY™.13,14 Lonafarnib was granted FDA approval on November 20, 2020, and is the first FDA-approved treatment for HGPS and other related progeroid laminopathies.13,15
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 638.822
Monoisotopic: 636.050229257 - Chemical Formula
- C27H31Br2ClN4O2
- Synonyms
- Lonafarnib
- Lonafarnibum
- External IDs
- SCH 66336
- SCH-66336
- SCH66336
Pharmacology
- Indication
Lonafarnib is a farnesyltransferase inhibitor indicated in patients aged 12 months and older with a body surface area of at least 0.39 m2 to reduce the risk of mortality associated with Hutchinson-Gilford progeria syndrome (HGPS). It is also indicated in this same population for the treatment of processing-deficient progeroid laminopathies that either involve a heterozygous LMNA mutation resulting in the accumulation of a progerin-like protein or homozygous/compound heterozygous mutations in ZMPSTE24.13
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prevention of Death •••••••••••• •••• ••••••• •••• •• •••• •• ••• ••••• ••••••• Treatment of Hutchinson-gilford progeria syndrome •••••••••••• ••••••• Treatment of Processing-deficient progeroid laminopathies •••••••••••• •••• ••••••• •••• •• •••• •• ••• ••••• ••••••• Treatment of Processing-deficient progeroid laminopathies •••••••••••• •••• ••••••• •••• •• •••• •• ••• ••••• ••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Lonafarnib is a direct farnesyl transferase inhibitor that reduces the farnesylation of numerous cellular proteins, including progerin, the aberrantly truncated form of lamin A that accumulates in progeroid laminopathies such as Hutchinson-Gilford progeria syndrome. Treatment with lonafarnib has been associated with electrolyte abnormalities, myelosuppression, and increased liver enzyme levels (AST/ALT), although causation remains unclear. Also, lonafarnib is known to cause nephrotoxicity in rats and rod-dependent low-light vision decline in monkeys at plasma levels similar to those achieved under recommended dosing guidelines in humans; patients taking lonafarnib should undergo regular monitoring for both renal and ophthalmological function. In addition, based on observations from animal studies with rats, monkeys, and rabbits with plasma drug concentrations approximately equal to those attained in humans, lonafarnib may cause both male and female fertility impairment and embryo-fetal toxicity.13
- Mechanism of action
Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in premature ageing, associated cardiovascular, cerebrovascular, and musculoskeletal effects and early death around 14 years of age.1,2,3,4 The LMNA gene encodes lamin A and lamin C, two proteins involved in nuclear integrity and function at the inner nuclear membrane. Under normal conditions, the 12-exon LMNA gene produces full-length prelamin A, which undergoes farnesylation of the C-terminal CaaX motif, followed by proteolytic cleavage of the terminal three amino acids (aaX) by the metalloproteinase ZMPSTE24, subsequent carboxymethylation, and finally removal of the last 15 amino acids to yield mature, unfarnesylated, lamin A protein.1,4 In HGPS, a single heterozygous C-to-T mutation at position 1824 results in a cryptic splice site that removes the last 150 nucleotides of exon 11 and a concomitant 50-amino acid deletion in the C-terminus of the prelamin A protein. This aberrant prelamin A protein, often called progerin, is permanently farnesylated but unable to complete maturation due to the removal of the second endoproteolytic cleavage site.1,4
Although the exact mechanism is unclear, progerin accumulation results in a host of adverse symptoms associated with ageing such as skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive.1,2,3,4,5 An additional notable effect of HGPS is increased vascular and peripheral calcification.6 Children affected by HGPS typically die due to myocardial infarction or stroke.5 Mechanistic understanding of HGPS remains unclear, although a recent study correlated progerin accumulation, telomere dysfunction, DNA damage-mediated inflammatory cytokine release, and HGPS symptoms, suggesting that the nuclear effects of progerin accumulation may result in pleiotropic downstream effects.7
Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), with a reported IC50 value of 1.9 nM; lonafarnib is specific for FTase, as it does not appreciably inhibit the related GGPT-1 enzyme at concentrations up to 50 μM.8 Inhibition of progerin farnesylation reduces progerin accumulation in the inner nuclear membrane, which subsequently slows the progression of HGPS and other progeroid laminopathies.1,9,10,13
Target Actions Organism AProtein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha inhibitorHumans AProtein farnesyltransferase subunit beta inhibitorHumans - Absorption
The absolute oral bioavailability of lonafarnib is unknown; in healthy subjects administration of either 75 or 100 mg of lonafarnib twice daily resulted in mean peak plasma concentrations (%CV) of 834 (32%) and 964 (32%) ng/mL, respectively. Twice daily administration of 115 mg/m2 lonafarnib in HGPS patients resulted in a median tmax of 2 hours (range 0-6), mean Cmax of 1777 ± 1083 ng/mL, mean AUC0-8hr of 9869 ± 6327 ng*hr/mL, and a mean AUCtau of 12365 ± 9135 ng*hr/mL. The corresponding values for a dose of 150 mg/m2 are: 4 hours (range 0-12), 2695 ± 1090 ng/mL, 16020 ± 4978 ng*hr/mL, and 19539 ± 6434 ng*hr/mL, respectively.13
Following a single oral dose of 75 mg in healthy subjects, the Cmax of lonafarnib decreased by 55% and 25%, and the AUC decreased by 29% and 21% for a high/low-fat meal compared to fasted conditions.13
- Volume of distribution
In healthy patients administered either 75 or 100 mg lonafarnib twice daily, the steady-state apparent volumes of distribution were 97.4 L and 87.8 L, respectively.13
- Protein binding
Lonafarnib exhibits in vitro plasma protein binding of ≥99% over a concentration range of 0.5-40.0 μg/mL.13
- Metabolism
Lonafarnib is metabolized in vitro primarily by CYP3A4/5 and partially by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.11,13 Formation of the primary metabolites involves oxidation and subsequent dehydration in the pendant piperidine ring.11,12
Hover over products below to view reaction partners
- Route of elimination
Up to 240 hours following oral administration of 104 mg [14C]-lonafarnib in fasted healthy subjects, approximately 62% and <1% of the initial radiolabeled dose was recovered in feces and urine, respectively. The two most prevalent metabolites were the active HM21 and HM17, which account for 14% and 15% of plasma radioactivity.13
- Half-life
Lonafarnib has a mean half-life of approximately 4-6 hours following oral administration of 100 mg twice daily in healthy subjects.13
- Clearance
Not Available
- Adverse Effects
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- Toxicity
Toxicity information regarding lonafarnib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as altered electrolyte, blood cell, and liver enzyme levels, retinal toxicity, nephrotoxicity, fertility impairment, and embryo-fetal toxicity. Symptomatic and supportive measures are recommended.13
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The metabolism of 1,2-Benzodiazepine can be decreased when combined with Lonafarnib. Abametapir The serum concentration of Lonafarnib can be increased when it is combined with Abametapir. Abatacept The metabolism of Lonafarnib can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Lonafarnib. Abiraterone The metabolism of Abiraterone can be decreased when combined with Lonafarnib. - Food Interactions
- Avoid grapefruit products. Co-administration with strong or moderate CYP3A inhibitors is contraindicated; avoid consuming grapefruit or Seville oranges.
- Take with food. Administration with food is recommended to reduce gastrointestinal adverse reactions. However, co-administration with food does affect lonafarnib absorption.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Sarasar
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zokinvy Capsule 75 mg Oral Eiger Bio Europe Limited 2022-08-02 Not applicable EU Zokinvy Capsule 50 mg/1 Oral Eiger BioPharmaceuticals, Inc. 2020-11-20 Not applicable US Zokinvy Capsule 50 mg Oral Eiger Bio Europe Limited 2022-08-02 Not applicable EU Zokinvy Capsule 75 mg/1 Oral Eiger BioPharmaceuticals, Inc. 2020-11-20 Not applicable US
Categories
- ATC Codes
- A16AX20 — Lonafarnib
- Drug Categories
- Alimentary Tract and Metabolism
- BCRP/ABCG2 Inhibitors
- Benzocycloheptenes
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2A6 Substrates
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2E1 Substrates
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strong)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Inhibitors
- Cytochrome P-450 CYP3A5 Inhibitors (strong)
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Farnesyltransferase Inhibitor
- Farnesyltransferase Inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- Organic Anion Transporting Polypeptide 1B1 Inhibitors
- Organic Anion Transporting Polypeptide 1B3 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Various Alimentary Tract and Metabolism Products
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzocycloheptapyridines. These are aromatic compounds containing a benzene ring and a pyridine ring fused to a seven membered carbocycle.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzocycloheptapyridines
- Sub Class
- Not Available
- Direct Parent
- Benzocycloheptapyridines
- Alternative Parents
- Piperidinecarboxamides / N-acylpiperidines / Pyridines and derivatives / Aryl bromides / Aryl chlorides / Benzenoids / Tertiary carboxylic acid amides / Heteroaromatic compounds / Ureas / Azacyclic compounds show 7 more
- Substituents
- 1-piperidinecarboxamide / Aromatic heteropolycyclic compound / Aryl bromide / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Benzocycloheptapyridine / Carbonic acid derivative / Carbonyl group show 19 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- IOW153004F
- CAS number
- 193275-84-2
- InChI Key
- DHMTURDWPRKSOA-RUZDIDTESA-N
- 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
- IUPAC Name
- 4-(2-{4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl}-2-oxoethyl)piperidine-1-carboxamide
- SMILES
- NC(=O)N1CCC(CC(=O)N2CCC(CC2)[C@H]2C3=C(CCC4=C2C(Br)=CC(Cl)=C4)C=C(Br)C=N3)CC1
References
- Synthesis Reference
Njoroge FG, Taveras AG, Kelly J, Remiszewski S, Mallams AK, Wolin R, Afonso A, Cooper AB, Rane DF, Liu YT, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez CS, del Rosario J, Connolly M, Wang J, Desai J, Rossman RR, Bishop WR, Patton R, Wang L, Kirschmeier P, Ganguly AK, et al.: (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998 Nov 19;41(24):4890-902.
- General References
- Cubria MB, Suarez S, Masoudi A, Oftadeh R, Kamalapathy P, DuBose A, Erdos MR, Cabral WA, Karim L, Collins FS, Snyder BD, Nazarian A: Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups. Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12029-12040. doi: 10.1073/pnas.1906713117. Epub 2020 May 13. [Article]
- Prakash A, Gordon LB, Kleinman ME, Gurary EB, Massaro J, D'Agostino R Sr, Kieran MW, Gerhard-Herman M, Smoot L: Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA Cardiol. 2018 Apr 1;3(4):326-334. doi: 10.1001/jamacardio.2017.5235. [Article]
- Ullrich NJ, Kieran MW, Miller DT, Gordon LB, Cho YJ, Silvera VM, Giobbie-Hurder A, Neuberg D, Kleinman ME: Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology. 2013 Jul 30;81(5):427-30. doi: 10.1212/WNL.0b013e31829d85c0. Epub 2013 Jun 28. [Article]
- Young SG, Yang SH, Davies BS, Jung HJ, Fong LG: Targeting protein prenylation in progeria. Sci Transl Med. 2013 Feb 6;5(171):171ps3. doi: 10.1126/scitranslmed.3005229. [Article]
- Xu S, Jin ZG: Hutchinson-Gilford Progeria Syndrome: Cardiovascular Pathologies and Potential Therapies. Trends Biochem Sci. 2019 Jul;44(7):561-564. doi: 10.1016/j.tibs.2019.03.010. Epub 2019 Apr 26. [Article]
- Gordon CM, Cleveland RH, Baltrusaitis K, Massaro J, D'Agostino RB Sr, Liang MG, Snyder B, Walters M, Li X, Braddock DT, Kleinman ME, Kieran MW, Gordon LB: Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome. Bone. 2019 Aug;125:103-111. doi: 10.1016/j.bone.2019.05.008. Epub 2019 May 8. [Article]
- Li Y, Zhou G, Bruno IG, Zhang N, Sho S, Tedone E, Lai TP, Cooke JP, Shay JW: Transient introduction of human telomerase mRNA improves hallmarks of progeria cells. Aging Cell. 2019 Aug;18(4):e12979. doi: 10.1111/acel.12979. Epub 2019 May 31. [Article]
- Njoroge FG, Taveras AG, Kelly J, Remiszewski S, Mallams AK, Wolin R, Afonso A, Cooper AB, Rane DF, Liu YT, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez CS, del Rosario J, Connolly M, Wang J, Desai J, Rossman RR, Bishop WR, Patton R, Wang L, Kirschmeier P, Ganguly AK, et al.: (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998 Nov 19;41(24):4890-902. [Article]
- Gordon LB, Shappell H, Massaro J, D'Agostino RB Sr, Brazier J, Campbell SE, Kleinman ME, Kieran MW: Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018 Apr 24;319(16):1687-1695. doi: 10.1001/jama.2018.3264. [Article]
- Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A, Snyder BD, Ullrich NJ, Silvera VM, Liang MG, Quinn N, Miller DT, Huh SY, Dowton AA, Littlefield K, Greer MM, Kieran MW: Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. doi: 10.1161/CIRCULATIONAHA.116.022188. [Article]
- Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
- Tong W, Chowdhury SK, Su AD, Feng W, Ghosal A, Alton KB: Identification of unstable metabolites of Lonafarnib using liquid chromatography-quadrupole time-of-flight mass spectrometry, stable isotope incorporation and ion source temperature alteration. J Mass Spectrom. 2006 Nov;41(11):1430-41. doi: 10.1002/jms.1114. [Article]
- FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
- Eiger Bio: Lonafarnib license agreement [Link]
- FDA Press Announcement: FDA Approves First Treatment for Hutchinson-Gilford Progeria Syndrome and Some Progeroid Laminopathies [Link]
- Cayman Chemical: lonafarnib MSDS [Link]
- EMA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
- External Links
- Human Metabolome Database
- HMDB0304871
- PubChem Compound
- 148195
- ChemSpider
- 130645
- BindingDB
- 14459
- 2467553
- ChEBI
- 47097
- ChEMBL
- CHEMBL298734
- ZINC
- ZINC000003950115
- PharmGKB
- PA166129466
- PDBe Ligand
- 336
- Wikipedia
- Lonafarnib
- PDB Entries
- 1o5m
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Hepatitis D, Chronic 1 3 Completed Treatment Hepatitis Delta Virus 1 3 Terminated Treatment Chronic Myelomonocytic Leukemia / Myelodysplastic Syndrome / Myelomonocytic 1 3 Terminated Treatment Metastatic Cancer / Non-Small Cell Lung Carcinoma 1 2 Active Not Recruiting Treatment Hutchinson-Gilford Progeria Syndrome 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 50 mg Capsule Oral 50 mg/1 Capsule Oral 75 mg Capsule Oral 75 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8828356 No 2014-09-09 2023-10-17 US US7838531 No 2010-11-23 2024-07-26 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility ~3mg/ml MSDS - Predicted Properties
Property Value Source Water Solubility 0.000829 mg/mL ALOGPS logP 5.34 ALOGPS logP 4.74 Chemaxon logS -5.9 ALOGPS pKa (Strongest Acidic) 15.75 Chemaxon pKa (Strongest Basic) 3.28 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 79.53 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 149.31 m3·mol-1 Chemaxon Polarizability 60.09 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9971 Blood Brain Barrier + 0.9837 Caco-2 permeable - 0.6451 P-glycoprotein substrate Substrate 0.6145 P-glycoprotein inhibitor I Inhibitor 0.8218 P-glycoprotein inhibitor II Non-inhibitor 0.7588 Renal organic cation transporter Inhibitor 0.6161 CYP450 2C9 substrate Non-substrate 0.849 CYP450 2D6 substrate Non-substrate 0.6877 CYP450 3A4 substrate Substrate 0.5869 CYP450 1A2 substrate Non-inhibitor 0.6897 CYP450 2C9 inhibitor Non-inhibitor 0.6924 CYP450 2D6 inhibitor Non-inhibitor 0.8235 CYP450 2C19 inhibitor Inhibitor 0.5078 CYP450 3A4 inhibitor Inhibitor 0.5372 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.776 Ames test Non AMES toxic 0.6428 Carcinogenicity Non-carcinogens 0.9177 Biodegradation Not ready biodegradable 0.9858 Rat acute toxicity 2.6286 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.7635 hERG inhibition (predictor II) Inhibitor 0.8517
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 214.94221 predictedDeepCCS 1.0 (2019) [M+H]+ 217.33778 predictedDeepCCS 1.0 (2019) [M+Na]+ 223.25032 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Lonafarnib inhibits farnesyl transferase with an IC50 of 1.9nM.
- General Function
- Rab geranylgeranyltransferase activity
- Specific Function
- Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex. Contributes to the transfer of a farnesyl or geranylgeranyl moiety from farnesyl or geranylgeranyl dipho...
- Gene Name
- FNTA
- Uniprot ID
- P49354
- Uniprot Name
- Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
- Molecular Weight
- 44408.32 Da
References
- Lee HY, Moon H, Chun KH, Chang YS, Hassan K, Ji L, Lotan R, Khuri FR, Hong WK: Effects of insulin-like growth factor binding protein-3 and farnesyltransferase inhibitor SCH66336 on Akt expression and apoptosis in non-small-cell lung cancer cells. J Natl Cancer Inst. 2004 Oct 20;96(20):1536-48. [Article]
- Medeiros BC, Landau HJ, Morrow M, Lockerbie RO, Pitts T, Eckhardt SG: The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines. Leukemia. 2007 Apr;21(4):739-46. Epub 2007 Feb 1. [Article]
- FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Lonafarnib inhibits farnesyl transferase with an IC50 of 1.9nM.
- General Function
- Zinc ion binding
- Specific Function
- Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C-terminus of several prote...
- Gene Name
- FNTB
- Uniprot ID
- P49356
- Uniprot Name
- Protein farnesyltransferase subunit beta
- Molecular Weight
- 48773.2 Da
References
- FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Oxygen binding
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- Curator comments
- Lonafarnib is primarily metabolized by CYP3A, and is also a potent time-dependent CYP3A inhibitor.
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Components:
Name | UniProt ID |
---|---|
Cytochrome P450 3A4 | P08684 |
Cytochrome P450 3A43 | Q9HB55 |
Cytochrome P450 3A5 | P20815 |
Cytochrome P450 3A7 | P24462 |
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
- Gene Name
- CYP2A6
- Uniprot ID
- P11509
- Uniprot Name
- Cytochrome P450 2A6
- Molecular Weight
- 56501.005 Da
References
- FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
- Gene Name
- CYP2E1
- Uniprot ID
- P05181
- Uniprot Name
- Cytochrome P450 2E1
- Molecular Weight
- 56848.42 Da
References
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Wang E, Casciano CN, Clement RP, Johnson WW: The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res. 2001 Oct 15;61(20):7525-9. [Article]
- Wang EJ, Johnson WW: The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. Chemotherapy. 2003 Dec;49(6):303-8. doi: 10.1159/000074531. [Article]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Organic anion transmembrane transporter activity
- Specific Function
- Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
- Gene Name
- ABCC2
- Uniprot ID
- Q92887
- Uniprot Name
- Canalicular multispecific organic anion transporter 1
- Molecular Weight
- 174205.64 Da
References
- Wang EJ, Johnson WW: The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. Chemotherapy. 2003 Dec;49(6):303-8. doi: 10.1159/000074531. [Article]
Drug created at March 19, 2008 16:33 / Updated at September 05, 2022 12:50