Identification

Name
Lonafarnib
Accession Number
DB06448
Description

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
Thumb
Weight
Average: 638.822
Monoisotopic: 636.050229257
Chemical Formula
C27H31Br2ClN4O2
Synonyms
  • Lonafarnib
  • Lonafarnibum
External IDs
  • SCH 66336
  • SCH-66336
  • SCH66336

Pharmacology

Pharmacology
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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

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AProtein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
inhibitor
Humans
AProtein farnesyltransferase subunit beta
inhibitor
Humans
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
Medicalerrors
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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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Lonafarnib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Lonafarnib can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Lonafarnib.
AbirateroneThe metabolism of Lonafarnib can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Lonafarnib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Lonafarnib.
AcetohexamideThe metabolism of Lonafarnib can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Lonafarnib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe metabolism of Lonafarnib can be decreased when combined with Acetylsalicylic acid.
AdalimumabThe metabolism of Lonafarnib can be increased when combined with Adalimumab.
Interactions
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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

Products
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International/Other Brands
Sarasar
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZokinvyCapsule50 mg/1OralEiger BioPharmaceuticals, Inc.2020-11-20Not applicableUS flag
ZokinvyCapsule75 mg/1OralEiger BioPharmaceuticals, Inc.2020-11-20Not applicableUS flag

Categories

Drug Categories
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

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[9.4.0.0³,⁸]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
  1. 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. [PubMed:32404427]
  2. 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. [PubMed:29466530]
  3. 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. [PubMed:23897869]
  4. 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. [PubMed:23390246]
  5. 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. [PubMed:31036409]
  6. 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. [PubMed:31077852]
  7. 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. [PubMed:31152494]
  8. 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. [PubMed:9822558]
  9. 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. [PubMed:29710166]
  10. 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. [PubMed:27400896]
  11. 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. [PubMed:16443667]
  12. 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. [PubMed:17051523]
  13. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
  14. Eiger Bio: Lonafarnib license agreement [Link]
  15. FDA Press Announcement: FDA Approves First Treatment for Hutchinson-Gilford Progeria Syndrome and Some Progeroid Laminopathies [Link]
  16. Cayman Chemical: lonafarnib MSDS [Link]
PubChem Compound
148195
ChemSpider
130645
BindingDB
14459
RxNav
2467553
ChEBI
47097
ChEMBL
CHEMBL298734
ZINC
ZINC000003950115
PharmGKB
PA166129466
PDBe Ligand
336
Wikipedia
Lonafarnib
PDB Entries
1o5m

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentHepatitis Delta Virus1
3TerminatedTreatmentLeukemia, Myelomonocytic, Chronic / Myelodysplasia / Myelodysplastic Syndromes (MDS) / Myelomonocytic1
3TerminatedTreatmentNeoplasm Metastases / Non-Small Cell Lung Carcinoma (NSCLC)1
2CompletedTreatmentBreast Cancer1
2CompletedTreatmentCancer, Bladder / Transitional Cell Cancer of the Renal Pelvis and Ureter / Urethral Cancer1
2CompletedTreatmentChronic Chronic myelogenous leukemia1
2CompletedTreatmentChronic Delta Hepatitis1
2CompletedTreatmentChronic Hepatitis D Infection2
2CompletedTreatmentGlioblastoma Multiforme (GBM)1
2CompletedTreatmentHepatitis D2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral50 mg/1
CapsuleOral75 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8828356No2003-10-172023-10-17US flag
US7838531No2004-07-262024-07-26US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility~3mg/mlMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.000829 mg/mLALOGPS
logP5.34ALOGPS
logP4.74ChemAxon
logS-5.9ALOGPS
pKa (Strongest Acidic)15.75ChemAxon
pKa (Strongest Basic)3.28ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area79.53 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity149.31 m3·mol-1ChemAxon
Polarizability60.09 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9971
Blood Brain Barrier+0.9837
Caco-2 permeable-0.6451
P-glycoprotein substrateSubstrate0.6145
P-glycoprotein inhibitor IInhibitor0.8218
P-glycoprotein inhibitor IINon-inhibitor0.7588
Renal organic cation transporterInhibitor0.6161
CYP450 2C9 substrateNon-substrate0.849
CYP450 2D6 substrateNon-substrate0.6877
CYP450 3A4 substrateSubstrate0.5869
CYP450 1A2 substrateNon-inhibitor0.6897
CYP450 2C9 inhibitorNon-inhibitor0.6924
CYP450 2D6 inhibitorNon-inhibitor0.8235
CYP450 2C19 inhibitorInhibitor0.5078
CYP450 3A4 inhibitorInhibitor0.5372
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.776
Ames testNon AMES toxic0.6428
CarcinogenicityNon-carcinogens0.9177
BiodegradationNot ready biodegradable0.9858
Rat acute toxicity2.6286 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7635
hERG inhibition (predictor II)Inhibitor0.8517
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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with our fully connected ADMET & drug target dataset.
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Accelerate your drug discovery research with our ADMET & drug target dataset
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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
  1. 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. [PubMed:15494604]
  2. 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. [PubMed:17268526]
  3. 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
  1. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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. [PubMed:16443667]
  2. Flockhart Table of Drug Interactions [Link]
  3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. 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. [PubMed:16443667]
  2. Flockhart Table of Drug Interactions [Link]
  3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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:
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. 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. [PubMed:16443667]
  2. Flockhart Table of Drug Interactions [Link]
  3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  4. 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
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
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
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
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
  1. 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
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. 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. [PubMed:11606389]
  2. 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. [PubMed:14671431]
  3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  4. 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
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. 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 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
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
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
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
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
  1. 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. [PubMed:14671431]

Drug created on March 19, 2008 16:33 / Updated on January 20, 2021 07:44