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Details

Stereochemistry ABSOLUTE
Molecular Formula C27H31Br2ClN4O2
Molecular Weight 638.8216
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LONAFARNIB

SMILES

C1Cc2cc(cnc2[C@]([H])(C3CCN(CC3)C(=O)CC4CCN(CC4)C(=N)O)c5c1cc(cc5Br)Cl)Br

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:: 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

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
Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status.
2001 Jun 1
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
Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336.
2001 Mar 1
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
Agents targeting ras signaling pathway.
2002
Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336.
2002 Aug 1
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
Targeting RAS signalling pathways in cancer therapy.
2003 Jan
Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase.
2003 Jan 2
Overcoming resistance to imatinib by combining targeted agents.
2003 Mar
Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line.
2003 Mar 1
Farnesyltransferase inhibitors--a novel approach in the treatment of advanced pancreatic carcinomas.
2003 Mar-Apr
Gateways to clinical trials.
2003 Nov
Farnesyltransferase inhibitors and their potential in the treatment of breast carcinoma.
2003 Oct
New targets for therapy in breast cancer: farnesyltransferase inhibitors.
2004
Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator.
2004 Aug 2
[Molecular pathogenesis of chronic myeloid leukemia and tyrosine kinase inhibitor].
2004 Jan
Gateways to clinical trials.
2004 Mar
Gateways to clinical trials.
2004 Sep
Gateways to clinical trials.
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
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
Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration.
2005 May 1
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
[Farnesyl transferase inhibitors--a novel agent for breast cancer].
2006 Apr
Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).
2006 Apr
Gateways to clinical trials.
2006 Jul-Aug
Identification of unstable metabolites of Lonafarnib using liquid chromatography-quadrupole time-of-flight mass spectrometry, stable isotope incorporation and ion source temperature alteration.
2006 Nov
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
2007 Apr
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.
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 [WHO-DD]
Common Name 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
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 [INN]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 411713
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
FDA ORPHAN DRUG 333411
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
EU-Orphan Drug EU/3/18/2118
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
NCI_THESAURUS C2020
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
Code System Code Type Description
WIKIPEDIA
LONAFARNIB
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
PUBCHEM
148195
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
NCI_THESAURUS
C1829
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
EPA CompTox
193275-84-2
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
CAS
193275-84-2
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
MERCK INDEX
M6892
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY Merck Index
FDA UNII
IOW153004F
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
MESH
C115354
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
EVMPD
SUB21038
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
ChEMBL
CHEMBL298734
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
DRUG BANK
DB06448
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
INN
8191
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY