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
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
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 |
DescriptionSources: http://adisinsight.springer.com/drugs/800009901Curator'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/
Sources: http://adisinsight.springer.com/drugs/800009901
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20718706 | https://www.ncbi.nlm.nih.gov/pubmed/21735117
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
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL2094108 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9822558 |
1.9 nM [IC50] | ||
Target ID: CHEMBL2095164 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9822558 |
50000.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
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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 |
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Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. | 2001 May |
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Farnesyl protein transferase inhibition: a novel approach to anti-tumor therapy. the discovery and development of SCH 66336. | 2001 Oct |
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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 |
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Gateways to clinical trials. | 2002 Jul-Aug |
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Farnesyl transferase inhibitors as anticancer agents. | 2002 Sep |
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The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. | 2003 Dec |
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Targeting RAS signalling pathways in cancer therapy. | 2003 Jan |
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Farnesyl transferase inhibitors in clinical development. | 2003 Jun |
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Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells. | 2003 Mar |
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Farnesyl transferase inhibitors in the treatment of breast cancer. | 2003 Mar |
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Gateways to clinical trials. | 2003 Nov |
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[Ras signaling pathway as a target for farnesyltransferase inhibitors--a new, promising prospects in the treatment for malignant disorders]. | 2004 |
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New targets for therapy in breast cancer: farnesyltransferase inhibitors. | 2004 |
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Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator. | 2004 Aug 2 |
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Synthesis of 5-bromopyridyl-2-magnesium chloride and its application in the synthesis of functionalized pyridines. | 2004 Dec 23 |
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In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines. | 2004 Feb |
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[Molecular pathogenesis of chronic myeloid leukemia and tyrosine kinase inhibitor]. | 2004 Jan |
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Cancer treatment with kinase inhibitors: what have we learnt from imatinib? | 2004 Jan 12 |
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Gateways to clinical trials. | 2004 Mar |
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Farnesyltransferase inhibition: who are the Aktors? | 2004 Nov |
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The farnesyltransferase inhibitor Lonafarnib induces growth arrest or apoptosis of human lung cancer cells without downregulation of Akt. | 2004 Nov |
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Gateways to clinical trials. | 2004 Sep |
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Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma. | 2005 Aug 1 |
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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 |
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Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro. | 2005 Jul |
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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 |
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The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. | 2005 May 1 |
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A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer. | 2005 May-Jun |
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Development of farnesyl transferase inhibitors: a review. | 2005 Sep |
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Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. | 2005 Sep 7 |
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Gateways to clinical trials. | 2006 Mar |
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Combination therapy with aromatase inhibitors: the next era of breast cancer treatment? | 2006 Sep 18 |
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Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function. | 2007 Apr |
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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 |
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The farnesyltransferase inhibitor lonafarnib induces CCAAT/enhancer-binding protein homologous protein-dependent expression of death receptor 5, leading to induction of apoptosis in human cancer cells. | 2007 Jun 29 |
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New agents for treatment of advanced transitional cell carcinoma. | 2007 May |
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Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level. | 2007 Sep 15 |
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Farnesyl transferase inhibitor resistance probed by target mutagenesis. | 2007 Sep 15 |
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Exploring three-dimensional quantitative structural activity relationship (3D-QSAR) analysis of SCH 66336 (Sarasar) analogues of farnesyltransferase inhibitors. | 2008 Jan |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT00916747
150 mg/m2 by mouth twice daily
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16006564
Several experiments with 1 µM SCH66336 resulted in an average 70% reduction in S6 phosphorylation.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 17 17:09:23 UTC 2022
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admin
on
Sat Dec 17 17:09:23 UTC 2022
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Record UNII |
IOW153004F
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Record Status |
Validated (UNII)
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Record Version |
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FDA ORPHAN DRUG |
411713
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FDA ORPHAN DRUG |
333411
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EU-Orphan Drug |
EU/3/18/2118
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NCI_THESAURUS |
C2020
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Code System | Code | Type | Description | ||
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LONAFARNIB
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148195
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C1829
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DTXSID90172927
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193275-84-2
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M6892
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IOW153004F
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2467553
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MM-63
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C115354
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SUB21038
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CHEMBL298734
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DB06448
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8191
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Related Record | Type | Details | ||
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METABOLIC ENZYME -> SUBSTRATE | |||
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METABOLIC ENZYME -> INHIBITOR |
Lonafarnib is a potent CYP3A time-dependent and mechanism-based inhibitor.
TIME-DEPENDENT INHIBITION
POTENCY
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TRANSPORTER -> INHIBITOR | |||
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METABOLIC ENZYME -> SUBSTRATE |
IN VITRO
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METABOLIC ENZYME -> SUBSTRATE | |||
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> SUBSTRATE |
Lonafarnib is likely a marginal substrate of P-gp.
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TARGET -> INHIBITOR |
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METABOLIC ENZYME -> SUBSTRATE |
IN VITRO
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METABOLIC ENZYME -> SUBSTRATE |
IN VITRO
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METABOLIC ENZYME -> SUBSTRATE |
IN VITRO
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METABOLIC ENZYME -> INHIBITOR | |||
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METABOLIC ENZYME -> SUBSTRATE |
IN VITRO
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METABOLIC ENZYME -> INHIBITOR | |||
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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 ?g/mL.
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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METABOLIC ENZYME -> SUBSTRATE |
MAJOR
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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IN HEALTHY SUBJECTS |
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Tmax | PHARMACOKINETIC |
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AT STEADY-STATE |
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Volume of Distribution | PHARMACOKINETIC |
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AT STEADY-STATE |
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Biological Half-life | PHARMACOKINETIC |
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IN HEALTHY SUBJECTS |
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Tmax | PHARMACOKINETIC |
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ORAL ADMINISTRATION TWICE DAILY |
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