WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H201760
CAS#: 193275-84-2
Description: Lonafarnib is a farnesyl transferase inhibitor. Structurely, it is also a synthetic tricyclic derivative of carboxamide with antineoplastic properties. Lonarfanib binds to and inhibits farnesyl transferase, an enzyme involved in the post-translational modification and activation of Ras proteins. Ras proteins participate in numerous signalling pathways (proliferation, cytoskeletal organization), and play an important role in oncogenesis. Mutated ras proteins have been found in a wide range of human cancers.
Hodoodo Cat#: H201760
Name: Lonafarnib
CAS#: 193275-84-2
Chemical Formula: C27H31Br2ClN4O2
Exact Mass: 636.05
Molecular Weight: 638.820
Elemental Analysis: C, 50.76; H, 4.89; Br, 25.02; Cl, 5.55; N, 8.77; O, 5.01
Synonym: SCH 66336; SCH-66336; SCH66336; Lonafarnib; US brand name: Sarasar.
IUPAC/Chemical Name: 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]-1-piperidinecarboxamide
InChi Key: DHMTURDWPRKSOA-RUZDIDTESA-N
InChi Code: 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
SMILES Code: O=C(N1CCC(CC(N2CCC([C@@H]3C4=C(Br)C=C(Cl)C=C4CCC5=CC(Br)=CN=C53)CC2)=O)CC1)N
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: Lonafarnib is a non-peptidomimetic inhibitor of farnesyl transferase, an enzyme responsible for the post-translational lipid modification of a wide variety of cellular proteins that are involved in the pathogenic pathways of various diseases including cancer and progeria. Although extensive clinical research indicates limited activity of lonafarnib in solid tumors, there is recent interest in combinations of farnesyl transferase inhibitors with imatinib or bortezomib in hematological malignancies and to investigate the role of lonafarnib in progeria. There is no evidence to support the use of lonafarnib in solid tumors. There is ongoing interest to explore lonafarnib for progeria and to investigate other farnesyl transferase inhibitors for chronic and acute leukemias. (copied from Expert Opin Investig Drugs. 2012 Jul;21(7):1043-55.(
| Biological target: | Lonafarnib inhibits the activities of H-ras, K-ras and N-ras with IC50 values of 1.9 nM, 5.2 nM and 2.8 nM, respectively. |
| In vitro activity: | Lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. Lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Reference: PLoS One. 2015 Apr 8;10(4):e0122830. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390146/ |
| In vivo activity: | Tau inclusions are a shared feature of many neurodegenerative conditions and tau mutations lead to frontotemporal dementia. Approaches to treatment of these conditions have focused directly on the tau protein by targeting its post-translational modifications, its levels and its tendency to aggregate. A novel regulatory pathway for tau degradation was discovered that operates through the Rhes protein, a GTPase. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced Rhes, attenuated behavioral abnormalities, significantly reduced atrophy, tau inclusions, sumoylation and ubiquitination, as well as microgliosis in the rTg4510 tauopathy mouse. Direct reduction of Rhes levels reproduced the results observed with lonafarnib. The mechanism of lonafarnib action, as mediated by Rhes to reduce tau pathology, operates through its lysosomal degradation. Reference: Sci Transl Med. 2019 Mar 27;11(485):eaat3005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961212/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 46.6 | 72.95 | |
| DMF | 14.0 | 21.91 | |
| Ethanol | 70.5 | 110.36 | |
| Ethanol:PBS (pH 7.2) (1:4) | 0.2 | 0.31 |
The following data is based on the product molecular weight 638.82 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D. Lonafarnib is a potential inhibitor for neovascularization. PLoS One. 2015 Apr 8;10(4):e0122830. doi: 10.1371/journal.pone.0122830. PMID: 25853815; PMCID: PMC4390146. 2. Hernandez I, Luna G, Rauch JN, Reis SA, Giroux M, Karch CM, Boctor D, Sibih YE, Storm NJ, Diaz A, Kaushik S, Zekanowski C, Kang AA, Hinman CR, Cerovac V, Guzman E, Zhou H, Haggarty SJ, Goate AM, Fisher SK, Cuervo AM, Kosik KS. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med. 2019 Mar 27;11(485):eaat3005. doi: 10.1126/scitranslmed.aat3005. PMID: 30918111; PMCID: PMC7961212. |
| In vitro protocol: | 1. Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D. Lonafarnib is a potential inhibitor for neovascularization. PLoS One. 2015 Apr 8;10(4):e0122830. doi: 10.1371/journal.pone.0122830. PMID: 25853815; PMCID: PMC4390146. |
| In vivo protocol: | 1. Hernandez I, Luna G, Rauch JN, Reis SA, Giroux M, Karch CM, Boctor D, Sibih YE, Storm NJ, Diaz A, Kaushik S, Zekanowski C, Kang AA, Hinman CR, Cerovac V, Guzman E, Zhou H, Haggarty SJ, Goate AM, Fisher SK, Cuervo AM, Kosik KS. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med. 2019 Mar 27;11(485):eaat3005. doi: 10.1126/scitranslmed.aat3005. PMID: 30918111; PMCID: PMC7961212. |
1: Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D. Lonafarnib is a potential inhibitor for neovascularization. PLoS One. 2015 Apr 8;10(4):e0122830. doi: 10.1371/journal.pone.0122830. eCollection 2015. PubMed PMID: 25853815.
2: Ullrich NJ, Kieran MW, Miller DT, Gordon LB, Cho YJ, Silvera VM, Giobbie-Hurder A, Neuberg D, Kleinman ME. Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology. 2013 Jul 30;81(5):427-30. doi: 10.1212/WNL.0b013e31829d85c0. Epub 2013 Jun 28. PubMed PMID: 23897869; PubMed Central PMCID: PMC3776537.
3: Yust-Katz S, Liu D, Yuan Y, Liu V, Kang S, Groves M, Puduvalli V, Levin V, Conrad C, Colman H, Hsu S, Yung WK, Gilbert MR. Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma. Cancer. 2013 Aug 1;119(15):2747-53. doi: 10.1002/cncr.28031. Epub 2013 Apr 30. PubMed PMID: 23633392; PubMed Central PMCID: PMC4001735.
4: Milojkovic Kerklaan B, Diéras V, Le Tourneau C, Mergui-Roelvink M, Huitema AD, Rosing H, Beijnen JH, Marreaud S, Govaerts AS, Piccart-Gebhart MJ, Schellens JH, Awada A. Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023. Cancer Chemother Pharmacol. 2013 Jan;71(1):53-62. doi: 10.1007/s00280-012-1972-1. Epub 2012 Sep 29. Erratum in: Cancer Chemother Pharmacol. 2013 Feb;71(2):553. Kerklaan, Bojana Milojkovic [corrected to Milojkovic Kerklaan, Bojana]. PubMed PMID: 23053259.
5: Wong NS, Morse MA. Lonafarnib for cancer and progeria. Expert Opin Investig Drugs. 2012 Jul;21(7):1043-55. doi: 10.1517/13543784.2012.688950. Epub 2012 May 24. Review. PubMed PMID: 22620979.
6: Meier W, du Bois A, Rau J, Gropp-Meier M, Baumann K, Huober J, Wollschlaeger K, Kreienberg R, Canzler U, Schmalfeldt B, Wimberger P, Richter B, Schröder W, Belau A, Stähle A, Burges A, Sehouli J. Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV. Gynecol Oncol. 2012 Aug;126(2):236-40. doi: 10.1016/j.ygyno.2012.04.050. Epub 2012 May 4. PubMed PMID: 22564713.
7: Wong NS, Meadows KL, Rosen LS, Adjei AA, Kaufmann SH, Morse MA, Petros WP, Zhu Y, Statkevich P, Cutler DL, Meyers ML, Hurwitz HI. A phase I multicenter study of continuous oral administration of lonafarnib (SCH 66336) and intravenous gemcitabine in patients with advanced cancer. Cancer Invest. 2011 Nov;29(9):617-25. doi: 10.3109/07357907.2011.621912. PubMed PMID: 22011284; PubMed Central PMCID: PMC4101887.
8: Marcuzzi A, De Leo L, Decorti G, Crovella S, Tommasini A, Pontillo A. The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency. Pediatr Res. 2011 Jul;70(1):78-82. doi: 10.1038/pr.2011.303. PubMed PMID: 21430599.
9: Kauh J, Chanel-Vos C, Escuin D, Fanucchi MP, Harvey RD, Saba N, Shin DM, Gal A, Pan L, Kutner M, Ramalingam SS, Bender L, Marcus A, Giannakakou P, Khuri FR. Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies. Cancer. 2011 Sep 1;117(17):4049-59. doi: 10.1002/cncr.26004. Epub 2011 Mar 1. PubMed PMID: 21365629; PubMed Central PMCID: PMC3131496.
10: Chaponis D, Barnes JW, Dellagatta JL, Kesari S, Fast E, Sauvageot C, Panagrahy D, Greene ER, Ramakrishna N, Wen PY, Kung AL, Stiles C, Kieran MW. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas. J Neurooncol. 2011 Aug;104(1):179-89. doi: 10.1007/s11060-010-0502-4. Epub 2011 Jan 19. PubMed PMID: 21246394.
11: Castaneda C, Meadows KL, Truax R, Morse MA, Kaufmann SH, Petros WP, Zhu Y, Statkevich P, Cutler DL, Hurwitz HI. Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011 Feb;67(2):455-63. doi: 10.1007/s00280-010-1488-5. Epub 2010 Oct 24. PubMed PMID: 20972873.
12: Niessner H, Beck D, Sinnberg T, Lasithiotakis K, Maczey E, Gogel J, Venturelli S, Berger A, Mauthe M, Toulany M, Flaherty K, Schaller M, Schadendorf D, Proikas-Cezanne T, Schittek B, Garbe C, Kulms D, Meier F. The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. J Invest Dermatol. 2011 Feb;131(2):468-79. doi: 10.1038/jid.2010.297. Epub 2010 Oct 14. PubMed PMID: 20944654.
13: Liu G, Taylor SA, Marrinan CH, Hsieh Y, Bishop WR, Kirschmeier P, Long BJ. Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models. Int J Cancer. 2009 Dec 1;125(11):2711-20. doi: 10.1002/ijc.24644. PubMed PMID: 19530253.
14: Hanrahan EO, Kies MS, Glisson BS, Khuri FR, Feng L, Tran HT, Ginsberg LE, Truong MT, Hong WK, Kim ES. A phase II study of Lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck. Am J Clin Oncol. 2009 Jun;32(3):274-9. doi: 10.1097/COC.0b013e318187dd57. PubMed PMID: 19433965.
15: Ravoet C, Mineur P, Robin V, Debusscher L, Bosly A, André M, El Housni H, Soree A, Bron D, Martiat P. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. Ann Hematol. 2008 Nov;87(11):881-5. doi: 10.1007/s00277-008-0536-2. Epub 2008 Jul 19. PubMed PMID: 18641985.
16: Feldman EJ, Cortes J, DeAngelo DJ, Holyoake T, Simonsson B, O'Brien SG, Reiffers J, Turner AR, Roboz GJ, Lipton JH, Maloisel F, Colombat P, Martinelli G, Nielsen JL, Petersdorf S, Guilhot F, Barker J, Kirschmeier P, Frank E, Statkevich P, Zhu Y, Loechner S, List A. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Leukemia. 2008 Sep;22(9):1707-11. doi: 10.1038/leu.2008.156. Epub 2008 Jun 12. PubMed PMID: 18548095.
17: Oh SH, Jin Q, Kim ES, Khuri FR, Lee HY. Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. Clin Cancer Res. 2008 Mar 1;14(5):1581-9. doi: 10.1158/1078-0432.CCR-07-0952. PubMed PMID: 18316583.
18: Taylor SA, Marrinan CH, Liu G, Nale L, Bishop WR, Kirschmeier P, Liu M, Long BJ. Combining the farnesyltransferase inhibitor lonafarnib with paclitaxel results in enhanced growth inhibitory effects on human ovarian cancer models in vitro and in vivo. Gynecol Oncol. 2008 Apr;109(1):97-106. doi: 10.1016/j.ygyno.2007.12.013. Epub 2008 Jan 31. PubMed PMID: 18237771.
19: Chow LQ, Eckhardt SG, O'Bryant CL, Schultz MK, Morrow M, Grolnic S, Basche M, Gore L. A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2008 Sep;62(4):631-46. Epub 2007 Dec 6. PubMed PMID: 18058098; PubMed Central PMCID: PMC2813768.
20: Zhu Y, Statkevich P, Cutler DL. Effect of food on the pharmacokinetics of lonafarnib (SCH 66336) following single and multiple doses. Int J Clin Pharmacol Ther. 2007 Oct;45(10):539-47. PubMed PMID: 17966839.
