LONAFARNIB

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 Search

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
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Protein farnesyltransferase 13 Target ID: CHEMBL2094108 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9822558	Inhibitor 8297		1.9 nM [IC50]
Geranylgeranyl transferase type I 7 Target ID: CHEMBL2095164 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9822558	Inhibitor 8297		50000.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Progeria 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22620979	Primary	Phase II 1132	Unknown Approved Use Unknown
Chronic hepatitis D 1 Sources: http://www.eigerbio.com/hepatitis-d/lonafarnib-clinical-studies/	Primary	Phase II 1132	Unknown Approved Use Unknown
Chronic myelogenous leukemia 22 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16342165	Primary	Phase II 1132	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
[Ras signaling pathway as a target for farnesyltransferase inhibitors--a new, promising prospects in the treatment for malignant disorders].	2004	15765763
New targets for therapy in breast cancer: farnesyltransferase inhibitors.	2004	15535857
Synthesis of 5-bromopyridyl-2-magnesium chloride and its application in the synthesis of functionalized pyridines.	2004 Dec 23	15606096
Farnesyltransferase inhibition: who are the Aktors?	2004 Nov	15640614
Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: possible mechanisms of action.	2004 Nov	15512806
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	15494604
Gateways to clinical trials.	2004 Sep	15538546
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	15996016
Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.	2005 Aug 1	16028213
Microtubule interactions with chemically diverse stabilizing agents: thermodynamics of binding to the paclitaxel site predicts cytotoxicity.	2005 Dec	16356844
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	16118318
Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia.	2005 Feb	15538404
Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro.	2005 Jul	15889158
Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells.	2005 Jul 1	15994961
Gateways to clinical trials.	2005 Mar	15834466
[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia].	2005 Mar	15820917
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	15772889
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	15911238
Farnesyltransferase inhibitors in myelodysplastic syndrome.	2005 May	15865870
Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.	2005 May	15857290
The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase.	2005 May 1	15867388
Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration.	2005 May 1	15609318
A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer.	2005 May-Jun	15907712
[Molecular targeted therapy for malignant brain tumors].	2005 Sep	16201575
Development of farnesyl transferase inhibitors: a review.	2005 Sep	16177281
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	16006564
Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.	2005 Sep 7	16145048
Myelodysplasia: when to treat and how.	2006	16516126
[Farnesyl transferase inhibitors--a novel agent for breast cancer].	2006 Apr	16613692
Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).	2006 Apr	16443667
A generalized response surface model with varying relative potency for assessing drug interaction.	2006 Dec	17156272
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	16428512
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	16342165
Gateways to clinical trials.	2006 Jul-Aug	16894408
Lonafarnib in cancer therapy.	2006 Jun	16732721
Gateways to clinical trials.	2006 Mar	16636723
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	17051523
Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?	2006 Sep 18	16926831
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.	2007 Apr	17431110
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	17268526
Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors.	2007 Jan 15	17255280
Farnesyltransferase inihibitors in hematologic malignancies.	2007 Jul	17293017
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	17634493
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	17493934
Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.	2007 Mar	16996129
New agents for treatment of advanced transitional cell carcinoma.	2007 May	17018703
Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib.	2007 Sep 15	17623836
Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level.	2007 Sep 15	17545504
Farnesyl transferase inhibitor resistance probed by target mutagenesis.	2007 Sep 15	17536018
Exploring three-dimensional quantitative structural activity relationship (3D-QSAR) analysis of SCH 66336 (Sarasar) analogues of farnesyltransferase inhibitors.	2008 Jan	17442459

Patents

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

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