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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

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

CNS Penetrant
2523
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.

Originator

Approval Year

2020
842
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8228
 1.9 nM [IC50]
Inhibitor
8228
 50000.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase II
1144
Unknown

Approved Use

Unknown
Primary
Phase II
1144
Unknown

Approved Use

Unknown
Primary
Phase II
1144
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
Farnesyltransferase inhibitors in breast cancer therapy.
2002
Implication of protein kinase B/Akt and Bcl-2/Bcl-XL suppression by the farnesyl transferase inhibitor SCH66336 in apoptosis induction in squamous carcinoma cells.
2003 Aug 15
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
Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase.
2003 Jan 2
Farnesyl transferase inhibitors in clinical development.
2003 Jun
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
Gateways to clinical trials.
2003 Nov
[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
Synthesis of 5-bromopyridyl-2-magnesium chloride and its application in the synthesis of functionalized pyridines.
2004 Dec 23
In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines.
2004 Feb
Cancer treatment with kinase inhibitors: what have we learnt from imatinib?
2004 Jan 12
Farnesyltransferase inhibitors as anticancer agents: critical crossroads.
2004 Jul
Gateways to clinical trials.
2004 Mar
Farnesyltransferase inhibition: who are the Aktors?
2004 Nov
Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: possible mechanisms of action.
2004 Nov
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
Gateways to clinical trials.
2004 Sep
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
Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.
2005 Aug 1
Microtubule interactions with chemically diverse stabilizing agents: thermodynamics of binding to the paclitaxel site predicts cytotoxicity.
2005 Dec
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
Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro.
2005 Jul
Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells.
2005 Jul 1
Gateways to clinical trials.
2005 Mar
[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia].
2005 Mar
Hit to Lead Success Stories--IBC Conference: Effective chemistry strategies for reducing attrition rates and speeding lead compounds into the pipeline. 31 January-1 February 2005, San Diego, CA, USA.
2005 Mar
Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers.
2005 May
Farnesyltransferase inhibitors in myelodysplastic syndrome.
2005 May
Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.
2005 May
The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase.
2005 May 1
Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration.
2005 May 1
A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer.
2005 May-Jun
[Molecular targeted therapy for malignant brain tumors].
2005 Sep
Development of farnesyl transferase inhibitors: a review.
2005 Sep
The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity.
2005 Sep 2
Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.
2005 Sep 7
Myelodysplasia: when to treat and how.
2006
Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).
2006 Apr
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
Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.
2006 Jan 15
Lonafarnib in cancer therapy.
2006 Jun
Gateways to clinical trials.
2006 Mar
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
Patents

Patents

US 5874442
1
WO 9723478
1

Sample Use Guides

In Vivo Use Guide
150 mg/m2 by mouth twice daily
Route of Administration: Oral
In Vitro Use Guide
Several experiments with 1 µM SCH66336 resulted in an average 70% reduction in S6 phosphorylation.
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
ACTIVE MOIETY
Structure of LONAFARNIB
NIH
NCATS
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