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 |
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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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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 |
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Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. | 2001 May |
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Current status of clinical trials of farnesyltransferase inhibitors. | 2001 Nov |
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Farnesyltransferase inhibitors in breast cancer therapy. | 2002 |
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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 |
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Gateways to clinical trials. | 2002 Jul-Aug |
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Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours. | 2002 Nov |
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Gateways to Clinical Trials. | 2002 Sep |
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Farnesyl transferase inhibitors: a major breakthrough in anticancer therapy? Naples, 12 April 2002. | 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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Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase. | 2003 Jan 2 |
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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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Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line. | 2003 Mar 1 |
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Farnesyltransferase inhibitors and their potential in the treatment of breast carcinoma. | 2003 Oct |
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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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A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. | 2004 Jan |
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Farnesyltransferase inhibition: who are the Aktors? | 2004 Nov |
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Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: possible mechanisms of action. | 2004 Nov |
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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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Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia. | 2005 Feb |
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[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia]. | 2005 Mar |
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Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications. | 2005 May |
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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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[Farnesyl transferase inhibitors--a novel agent for breast cancer]. | 2006 Apr |
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A generalized response surface model with varying relative potency for assessing drug interaction. | 2006 Dec |
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Gateways to clinical trials. | 2006 Jul-Aug |
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Combination therapy with aromatase inhibitors: the next era of breast cancer treatment? | 2006 Sep 18 |
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Farnesyltransferase inihibitors in hematologic malignancies. | 2007 Jul |
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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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Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma. | 2007 Mar |
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New agents for treatment of advanced transitional cell carcinoma. | 2007 May |
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
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on
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Record UNII |
IOW153004F
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Record Status |
Validated (UNII)
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FDA ORPHAN DRUG |
411713
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EU-Orphan Drug |
EU/3/18/2118
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NCI_THESAURUS |
C2020
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FDA ORPHAN DRUG |
333411
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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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100000087350
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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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47097
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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 μg/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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