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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
Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.
2001 May
An anion-induced regio- and chemoselective acylation and its application to the synthesis of an anticancer agent.
2001 Nov 15
Farnesyltransferase inhibitors in breast cancer therapy.
2002
Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336.
2002 Aug 1
Exploring the role of bromine at C(10) of (+)-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- oxoethyl]-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inhibitors of farnesyl protein transferase.
2002 Aug 29
Inhibitors of farnesyl protein transferase and MEK1,2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras.
2002 Feb 15
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
Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours.
2002 Nov
Farnesyl transferase inhibitors as anticancer agents.
2002 Sep
Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations.
2003
Farnesyltransferase inhibitors in acute myeloid leukemia and myelodysplastic syndromes.
2003 Aug
The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2.
2003 Dec
Targeting RAS signalling pathways in cancer therapy.
2003 Jan
High-performance liquid chromatography-atmospheric pressure photoionization/tandem mass spectrometric analysis for small molecules in plasma.
2003 Jul 1
Farnesyl transferase inhibitors in clinical development.
2003 Jun
Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells.
2003 Jun 10
Overcoming resistance to imatinib by combining targeted agents.
2003 Mar
Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells.
2003 Mar
Farnesyl transferase inhibitors in the treatment of breast cancer.
2003 Mar
Preclinical and clinical evaluation of farnesyltransferase inhibitors.
2003 Mar
Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line.
2003 Mar 1
Farnesyltransferase inhibitors as anticancer agents: critical crossroads.
2004 Jul
Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.
2004 May 1
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.
2004 Oct 20
Quantitative analysis of the farnesyl transferase inhibitor lonafarnib (Sarasartrade mark, SCH66336) in human plasma using high-performance liquid chromatography coupled with tandem mass spectrometry.
2005
The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT.
2005 Dec 15
The effect of the farnesyl protein transferase inhibitor SCH66336 on isoprenylation and signalling by the prostacyclin receptor.
2005 Feb 15
Gateways to clinical trials.
2005 Mar
Farnesyltransferase inhibitors in myelodysplastic syndrome.
2005 May
[Molecular targeted therapy for malignant brain tumors].
2005 Sep
Development of farnesyl transferase inhibitors: a review.
2005 Sep
Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.
2005 Sep 7
Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma.
2006 Jan 15
Gateways to clinical trials.
2006 Jul-Aug
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
2007 Apr
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.
2007 Apr
Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors.
2007 Jan 15
Farnesyltransferase inihibitors in hematologic malignancies.
2007 Jul
Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.
2007 Mar
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 Thu Jul 06 10:29:40 UTC 2023
Edited
by admin
on Thu Jul 06 10:29:40 UTC 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 Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
EU-Orphan Drug EU/3/18/2118
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
NCI_THESAURUS C2020
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
FDA ORPHAN DRUG 333411
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
Code System Code Type Description
WIKIPEDIA
LONAFARNIB
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
PUBCHEM
148195
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
NCI_THESAURUS
C1829
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
SMS_ID
100000087350
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
EPA CompTox
DTXSID90172927
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
CAS
193275-84-2
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
MERCK INDEX
M6892
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY Merck Index
FDA UNII
IOW153004F
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
RXCUI
2467553
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
USAN
MM-63
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
MESH
C115354
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
EVMPD
SUB21038
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
DAILYMED
IOW153004F
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
ChEMBL
CHEMBL298734
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
DRUG BANK
DB06448
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
CHEBI
47097
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 2023
PRIMARY
INN
8191
Created by admin on Thu Jul 06 10:29:40 UTC 2023 , Edited by admin on Thu Jul 06 10:29:40 UTC 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