Lonafarnib

Catalog No.S2797

Lonafarnib is an orally bioavailable FPTase inhibitor for H-ras, K-ras-4B and N-ras with IC50 of 1.9 nM, 5.2 nM and 2.8 nM in cell-free assays, respectively. Phase 3.

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Lonafarnib Chemical Structure

Lonafarnib Chemical Structure
Molecular Weight: 638.82

Validation & Quality Control

Quality Control & MSDS

Related Compound Libraries

Lonafarnib is available in the following compound libraries:

Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Lonafarnib is an orally bioavailable FPTase inhibitor for H-ras, K-ras-4B and N-ras with IC50 of 1.9 nM, 5.2 nM and 2.8 nM in cell-free assays, respectively. Phase 3.
Targets H-ras [1]
(Cell-free assay)
N-ras [1]
(Cell-free assay)
K-ras-4B [1]
(Cell-free assay)
IC50 1.9 nM 2.8 nM 5.2 nM
In vitro SCH66336 at concentration ranging from 0.1 μM to 8 μM suppress growth and induce apoptosis of human head and neck squamous carcinoma cells (HNSCC) in a dose and time dependent manner. SCH66336 (8 μM) suppresses protein kinase B/Akt activity as well as the phosphorylation of the Akt substrates glycogen synthase kinase (GSK)-3β, forkhead transcription factor, and BAD in SqCC/Y1 cells. [2] SCH66336 demonstrate variable antiproliferative effects against the cell lines, with IC50 ranging from 0.6 μM to 32.3 μM. [3] Lonafarnib induces a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter, thus induces CHOP-dependent DR5 up-regulation. Lonafarnib (< 10 μM) activates caspase-8 and its downstream caspases, thus induces caspase-8-dependent apoptosis in H1792 cells. Lonafarnib (5 μM) up-regulate DR5 expression, increase cell-surface DR5 distribution, and enhance tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in H1792 cells.[4]
In vivo SCH66336 inhibits HTBI77 human lung carcinoma xenograft growth in nude mice in a dose-dependent fashion. [1] SCH66336 dosed at 50 mg/kg p.o. bid by oral gavage inhibits tumor growth with up to 69% growth inhibition after 21 days of treatment in NOD/SCID mice bearing s.c. flank XEN01, XEN05 or XEN08 GBM xenografts. [3]
Features

Protocol(Only for Reference)

Cell Assay: [2]

Cell lines UMSCC10B, UMSCC14B, UMSCC17B, UMSCC22B, and UMSCC35, UMSCC38 cell lines
Concentrations 0.1 μM - 8 μM
Incubation Time 24 hours
Method The cells are seeded in 96-well cell-culture cluster plates at a density that allowed control cultures to grow exponentially for 5 days. After 24 hours, the cells are treated with different concentrations of SCH66336. SCH66336 is dissolved in DMSO. Control cultures received the same amount of DMSO as the treated cultures do. Cell numbers are estimated after 5 days of treatment by SRB assay. The percentage of growth inhibition is calculated by using the equation: percentage growth inhibition = (1 − At/Ac) × 100, where At and Ac represent the absorbance in treated and control cultures, respectively. The drug concentration causing a 50% cell growth inhibition (IC50), is determined by interpolation from dose-response curves.

Animal Study: [3]

Animal Models NOD/SCID mice between 6–12 weeks of age
Formulation 20% (w/v) HPβCD
Dosages 50 mg/kg
Administration p.o. bid by oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Liu M, et al. Cancer Res, 1998, 58(21), 4947-4956.

[2] Chun KH, et al. Cancer Res, 2003, 63(16), 4796-4800.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-18)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02579044 Recruiting Progeria Childrens Hospital Boston December 2015 Phase 1|Phase 2
NCT02527707 Active, not recruiting Chronic Delta Hepatitis Eiger BioPharmaceuticals|Hannover Medical School September 2015 Phase 2
NCT02511431 Recruiting Hepatitis D National Institute of Diabetes and Digestive and Kidney D  ...more National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|National Institutes of Health Clinical Center (CC) July 2015 Phase 2
NCT02430194 Recruiting Chronic Hepatitis D Infection Eiger BioPharmaceuticals|Ankara University December 2014 Phase 2
NCT02430181 Completed Chronic Hepatitis D Infection Eiger BioPharmaceuticals November 2014 Phase 2

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Chemical Information

Download Lonafarnib SDF
Molecular Weight (MW) 638.82
Formula

C27H31Br2ClN4O2

CAS No. 193275-84-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms SCH66336
Solubility (25°C) * In vitro DMSO 127 mg/mL (198.8 mM)
Ethanol 127 mg/mL (198.8 mM)
Water <1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 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]-

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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