U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C27H31Br2ClN4O2
Molecular Weight 638.822
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LONAFARNIB

SMILES

NC(=O)N1CCC(CC(=O)N2CCC(CC2)[C@H]3C4=C(CCC5=C3C(Br)=CC(Cl)=C5)C=C(Br)C=N4)CC1

InChI

InChIKey=DHMTURDWPRKSOA-RUZDIDTESA-N
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

HIDE SMILES / InChI

Molecular Formula C27H31Br2ClN4O2
Molecular Weight 638.822
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pubmed/22620979 http://www.eigerbio.com/hepatitis-d/about-lonafarnib/

Lonafarnib is a well-characterized, late-stage, orally active inhibitor of farnesyl transferase, an enzyme involved in modification of proteins through a process called prenylation. It is Investigated for use/treatment in Progeria, Cancer, Hepatitis D. Lonafarnib completely inhibits Rheb prenylation and phosphorylation of S6 ribosomal protein in cell culture, indicating a lack of alternative Rheb prenylation. Other groups have demonstrated that inhibition of protein synthesis via inactivation of eukaryotic elongation factor (eEF2) could be an alternate mechanism of lonafarnib induced growth inhibition that is independent of RAS/p70S6K eEF. Adverse effects included fatigue, diarrhea, dyspnea and neutropenia and respiratory insufficiency.

CNS Activity

Curator's Comment: The results indicated that lonafarnib appeared to be well-tolerated, able to cross blood-brain barrier and to show modest antitumor effects.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
1.9 nM [IC50]
50000.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.
2001 Feb 15
Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.
2001 Mar 1
Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.
2001 May
Current status of clinical trials of farnesyltransferase inhibitors.
2001 Nov
Farnesyltransferase inhibitors in breast cancer therapy.
2002
A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan.
2002 Jul
Gateways to clinical trials.
2002 Jul-Aug
Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours.
2002 Nov
Gateways to Clinical Trials.
2002 Sep
Farnesyl transferase inhibitors: a major breakthrough in anticancer therapy? Naples, 12 April 2002.
2002 Sep
The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2.
2003 Dec
Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase.
2003 Jan 2
Farnesyl transferase inhibitors in clinical development.
2003 Jun
Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells.
2003 Mar
Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line.
2003 Mar 1
Farnesyltransferase inhibitors and their potential in the treatment of breast carcinoma.
2003 Oct
[Ras signaling pathway as a target for farnesyltransferase inhibitors--a new, promising prospects in the treatment for malignant disorders].
2004
New targets for therapy in breast cancer: farnesyltransferase inhibitors.
2004
A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl.
2004 Jan
Farnesyltransferase inhibition: who are the Aktors?
2004 Nov
Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: possible mechanisms of action.
2004 Nov
Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.
2005 Aug 1
Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia.
2005 Feb
[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia].
2005 Mar
Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.
2005 May
Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.
2005 Sep 7
[Farnesyl transferase inhibitors--a novel agent for breast cancer].
2006 Apr
A generalized response surface model with varying relative potency for assessing drug interaction.
2006 Dec
Gateways to clinical trials.
2006 Jul-Aug
Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?
2006 Sep 18
Farnesyltransferase inihibitors in hematologic malignancies.
2007 Jul
Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium Study.
2007 Jul 20
Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.
2007 Mar
New agents for treatment of advanced transitional cell carcinoma.
2007 May
Patents

Sample Use Guides

150 mg/m2 by mouth twice daily
Route of Administration: Oral
Several experiments with 1 µM SCH66336 resulted in an average 70% reduction in S6 phosphorylation.
Substance Class Chemical
Created
by admin
on Sat Dec 16 04:37:30 GMT 2023
Edited
by admin
on Sat Dec 16 04:37:30 GMT 2023
Record UNII
IOW153004F
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LONAFARNIB
INN   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
SCH-66336
Code English
SARASAR
Brand Name English
SCH66336
Code English
LONAFARNIB [MI]
Common Name English
SCH 66336
Code English
1-PIPERIDINECARBOXAMIDE, 4-(2-(4-((11R-3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDIN-11-YL)-1-PIPERIDINYL)-2-OXOETHYL)-
Common Name English
LONAFARNIB [ORANGE BOOK]
Common Name English
ZOKINVY
Brand Name English
LONAFARNIB [USAN]
Common Name English
(+)-4-(2-(4-(11R)-3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDIN-11-YL)-PIPERIDIN-1-YL))-2-OXOETHYL)-PIPERIDINE-1-CARBOXAMIDE
Common Name English
Lonafarnib [WHO-DD]
Common Name English
lonafarnib [INN]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 411713
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
EU-Orphan Drug EU/3/18/2118
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
NCI_THESAURUS C2020
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
FDA ORPHAN DRUG 333411
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
Code System Code Type Description
WIKIPEDIA
LONAFARNIB
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
PUBCHEM
148195
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
NCI_THESAURUS
C1829
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
SMS_ID
100000087350
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
EPA CompTox
DTXSID90172927
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
CAS
193275-84-2
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
MERCK INDEX
m6892
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY Merck Index
FDA UNII
IOW153004F
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
RXCUI
2467553
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
USAN
MM-63
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
MESH
C115354
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
EVMPD
SUB21038
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
DAILYMED
IOW153004F
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
ChEMBL
CHEMBL298734
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
DRUG BANK
DB06448
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
CHEBI
47097
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
INN
8191
Created by admin on Sat Dec 16 04:37:31 GMT 2023 , Edited by admin on Sat Dec 16 04:37:31 GMT 2023
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
METABOLIC ENZYME -> INHIBITOR
Lonafarnib is a potent CYP3A time-dependent and mechanism-based inhibitor.
TIME-DEPENDENT INHIBITION
POTENCY
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> SUBSTRATE
TRANSPORTER -> INHIBITOR
TRANSPORTER -> SUBSTRATE
Lonafarnib is likely a marginal substrate of P-gp.
TARGET -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> INHIBITOR
BINDER->LIGAND
In vitro plasma protein binding of lonafarnib was greater than or equal to 99% over the concentration range between 0.5 to 40.0 μg/mL.
TRANSPORTER -> INHIBITOR
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
MAJOR
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC IN HEALTHY SUBJECTS

ORAL ADMINISTRATION DOSE

AT STEADY-STATE

Tmax PHARMACOKINETIC AT STEADY-STATE

DOSE

ORAL ADMINISTRATION TWICE DAILY

Volume of Distribution PHARMACOKINETIC AT STEADY-STATE

ORAL ADMINISTRATION TWICE DAILY

IN HEALTHY SUBJECTS

Biological Half-life PHARMACOKINETIC IN HEALTHY SUBJECTS

ORAL ADMINISTRATION TWICE DAILY

Tmax PHARMACOKINETIC ORAL ADMINISTRATION TWICE DAILY

AT STEADY-STATE

DOSE