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 |
DescriptionCurator'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/
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 |
|---|---|---|---|
Target ID: CHEMBL2094108 |
1.9 nM [IC50] | ||
Target ID: CHEMBL2095164 |
50000.0 nM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. | 2001 May |
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| An anion-induced regio- and chemoselective acylation and its application to the synthesis of an anticancer agent. | 2001 Nov 15 |
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| Farnesyltransferase inhibitors in breast cancer therapy. | 2002 |
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| Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. | 2002 Aug 1 |
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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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| Inhibitors of farnesyl protein transferase and MEK1,2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras. | 2002 Feb 15 |
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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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| 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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| Farnesyl transferase inhibitors as anticancer agents. | 2002 Sep |
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| Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations. | 2003 |
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| Farnesyltransferase inhibitors in acute myeloid leukemia and myelodysplastic syndromes. | 2003 Aug |
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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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| High-performance liquid chromatography-atmospheric pressure photoionization/tandem mass spectrometric analysis for small molecules in plasma. | 2003 Jul 1 |
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| Farnesyl transferase inhibitors in clinical development. | 2003 Jun |
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| Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells. | 2003 Jun 10 |
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| Overcoming resistance to imatinib by combining targeted agents. | 2003 Mar |
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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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| Preclinical and clinical evaluation of farnesyltransferase inhibitors. | 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 as anticancer agents: critical crossroads. | 2004 Jul |
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| 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
| Substance Class |
Chemical
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IOW153004F
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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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C2020
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FDA ORPHAN DRUG |
333411
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LONAFARNIB
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148195
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M6892
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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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ACTIVE MOIETY |
| Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
|---|---|---|---|---|---|---|
| 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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