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MedKoo Cat#: 202930 | Name: Tipifarnib
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Tipifarnib, also known as R115777, is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It inhibits prenylation of the CxxX tail motif, which allows Ras to bind to the membrane where it is active. Without this step the protein cannot function.

Chemical Structure

Tipifarnib
Tipifarnib
CAS#192185-72-1

Theoretical Analysis

MedKoo Cat#: 202930

Name: Tipifarnib

CAS#: 192185-72-1

Chemical Formula: C27H22Cl2N4O

Exact Mass: 488.1171

Molecular Weight: 489.40

Elemental Analysis: C, 66.26; H, 4.53; Cl, 14.49; N, 11.45; O, 3.27

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to ship
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,250.00 Ready to Ship
500mg USD 2,850.00 Ready to ship
1g USD 3,950.00 Ready to ship
2g USD 6,450.00 Ready to ship
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Related CAS #
No Data
Synonym
R115777; R 115777; R-115777; LX81; NSC702818; D03720; Tipifarnib; trade name Zarnestra
IUPAC/Chemical Name
(R)-6-(Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone
InChi Key
PLHJCIYEEKOWNM-HHHXNRCGSA-N
InChi Code
InChI=1S/C27H22Cl2N4O/c1-32-16-31-15-25(32)27(30,18-6-9-20(28)10-7-18)19-8-11-24-23(13-19)22(14-26(34)33(24)2)17-4-3-5-21(29)12-17/h3-16H,30H2,1-2H3/t27-/m1/s1
SMILES Code
O=C1N(C)C2=C(C=C([C@@](C3=CC=C(Cl)C=C3)(N)C4=CN=CN4C)C=C2)C(C5=CC=CC(Cl)=C5)=C1
Appearance
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
>5 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
For treatment of progressive plexiform neurofibromas associated with Neurofibromatosis type I, it successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two. The compound was discovered by and is under investigation by Johnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777. Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005. In June 2005, the FDA issued a "not approvable" letter for tipifarnib.
Biological target:
Tipifarnib (IND 58359) binds to and inhibits farnesyltransferase (FTase) with an IC50 of 0.86 nM.
In vitro activity:
In a human leukemia cell line THP-1, tipifarnib inhibited lipopolysaccharide (LPS)-induced transcription of chemokines [monocyte chemotactic protein (MCP)-1 and MCP-2], cytokines [interleukin (IL)-1beta, IL-6, and interferon (IFN)beta], signaling molecules (MyD88 and STAT-1), proteases [matrix metalloproteinase (MMP-9)], and receptors (urokinase receptor). Tipifarnib also inhibited LPS-induced secretion of MMP-9, IL-6, MCP-1, and IL-1beta in THP-1 cells. In primary human peripheral blood mononuclear cells, dose-dependent inhibition of LPS-induced tumor necrosis factor (TNF)-alpha, IL-6, MCP-1, and IL-1beta by tipifarnib was observed with no evidence of cytotoxicity. Reference: J Pharmacol Exp Ther. 2006 Apr;317(1):53-60. https://jpet.aspetjournals.org/content/317/1/53.long
In vivo activity:
Whether tipifarnib is sufficient to display tumor suppressive effects in vivo was investigated in athymic nude mice and NOD-SCID mice. Tipifarnib significantly halted tumor growth from as early as three days after treatment initiation (n=6, p<0.001) (Fig. 4A–C). Tipifarnib reduced pERK in both xenograft models (Fig. 4D). Moreover, IHC for cleaved Caspase 3 and IF for Ki67 showed that, inhibition of HRAS by tipifarnib caused increased apoptosis and a reduction of cell proliferation in HNSCC tumors (Fig. 4D). Reference: Mol Cancer Ther. 2020 Sep;19(9):1784-1796. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484242/
Solvent mg/mL mM
Solubility
DMSO 42.6 86.96
Ethanol 7.4 15.12
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 489.40 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.

Recalculate based on batch purity %
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. Xue X, Lai KT, Huang JF, Gu Y, Karlsson L, Fourie A. Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib. J Pharmacol Exp Ther. 2006 Apr;317(1):53-60. doi: 10.1124/jpet.105.095976. Epub 2005 Dec 13. PMID: 16352705. 2. Kotsianidis I, Bazdiara I, Anastasiades A, Spanoudakis E, Pantelidou D, Margaritis D, Bourikas G, De Coster R, De Porre P, Tsatalas C. In vitro effects of the farnesyltransferase inhibitor tipifarnib on myelodysplastic syndrome progenitors. Acta Haematol. 2008;120(1):51-6. doi: 10.1159/000158577. Epub 2008 Sep 30. PMID: 18824842. 3. Gilardi M, Wang Z, Proietto M, Chillà A, Calleja-Valera JL, Goto Y, Vanoni M, Janes MR, Mikulski Z, Gualberto A, Molinolo AA, Ferrara N, Gutkind JS, Burrows F. Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas. Mol Cancer Ther. 2020 Sep;19(9):1784-1796. doi: 10.1158/1535-7163.MCT-19-0958. Epub 2020 Jul 29. PMID: 32727882; PMCID: PMC7484242. 4. Guo J, Shirozu K, Akahoshi T, Mizuta Y, Murata M, Yamaura K. The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A. Int Immunopharmacol. 2020 Jun;83:106462. doi: 10.1016/j.intimp.2020.106462. Epub 2020 Apr 3. PMID: 32251961.
In vitro protocol:
1. Xue X, Lai KT, Huang JF, Gu Y, Karlsson L, Fourie A. Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib. J Pharmacol Exp Ther. 2006 Apr;317(1):53-60. doi: 10.1124/jpet.105.095976. Epub 2005 Dec 13. PMID: 16352705. 2. Kotsianidis I, Bazdiara I, Anastasiades A, Spanoudakis E, Pantelidou D, Margaritis D, Bourikas G, De Coster R, De Porre P, Tsatalas C. In vitro effects of the farnesyltransferase inhibitor tipifarnib on myelodysplastic syndrome progenitors. Acta Haematol. 2008;120(1):51-6. doi: 10.1159/000158577. Epub 2008 Sep 30. PMID: 18824842.
In vivo protocol:
1. Gilardi M, Wang Z, Proietto M, Chillà A, Calleja-Valera JL, Goto Y, Vanoni M, Janes MR, Mikulski Z, Gualberto A, Molinolo AA, Ferrara N, Gutkind JS, Burrows F. Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas. Mol Cancer Ther. 2020 Sep;19(9):1784-1796. doi: 10.1158/1535-7163.MCT-19-0958. Epub 2020 Jul 29. PMID: 32727882; PMCID: PMC7484242. 2. Guo J, Shirozu K, Akahoshi T, Mizuta Y, Murata M, Yamaura K. The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A. Int Immunopharmacol. 2020 Jun;83:106462. doi: 10.1016/j.intimp.2020.106462. Epub 2020 Apr 3. PMID: 32251961.
1: Jagadeeshan S, Suryamohan K, Shin N, Mathukkada S, Boyko A, Melikhova D, Tsareva A, Yunusova L, Pravdivtseva E, Stupichev D, Shaposhnikov K, Peterson A, Bednyagin L, Shugaev-Mendosa E, Kessler L, Burrows F, Ho AL, Agrawal N, Pearson AT, Izumchenko E, Cole G, Elkabets M, Rosenberg AJ. Evolutionary dynamics of tipifarnib in HRAS mutated head and neck squamous cell carcinoma. Oral Oncol. 2024 Feb;149:106688. doi: 10.1016/j.oraloncology.2024.106688. Epub 2024 Jan 13. PMID: 38219706. 2: Smith AE, Chan S, Wang Z, McCloskey A, Reilly Q, Wang JZ, Patel HV, Koshizuka K, Soifer HS, Kessler L, Dayoub A, Villaflor V, Adkins DR, Bruce JY, Ho AL, Perez CA, Hanna GJ, Gascó Hernández A, Saunders A, Dale S, Gutkind JS, Burrows F, Malik S. Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity. Cancer Res. 2023 Oct 2;83(19):3252-3263. doi: 10.1158/0008-5472.CAN-23-0282. PMID: 37339176; PMCID: PMC10543974. 3: Liu X, Wills CA, Chen L, Zhang J, Zhao Y, Zhou M, Sundstrom JM, Schell T, Spiegelman VS, Young MM, Wang HG. Small extracellular vesicles induce resistance to anti-GD2 immunotherapy unveiling tipifarnib as an adjunct to neuroblastoma immunotherapy. J Immunother Cancer. 2022 Apr;10(4):e004399. doi: 10.1136/jitc-2021-004399. PMID: 35483745; PMCID: PMC9052051. 4: Greenberg JW, Kim H, Ahn M, Moustafa AA, Zhou H, Barata PC, Boulares AH, Abdel-Mageed AB, Krane LS. Combination of Tipifarnib and Sunitinib Overcomes Renal Cell Carcinoma Resistance to Tyrosine Kinase Inhibitors via Tumor-Derived Exosome and T Cell Modulation. Cancers (Basel). 2022 Feb 11;14(4):903. doi: 10.3390/cancers14040903. PMID: 35205655; PMCID: PMC8870174. 5: Luger SM, Wang VX, Rowe JM, Litzow MR, Paietta E, Ketterling RP, Lazarus H, Rybka WB, Craig MD, Karp J, Cooper BW, Makary AZ, Kaminer LS, Appelbaum FR, Larson RA, Tallman MS. Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial. Leuk Res. 2021 Dec;111:106736. doi: 10.1016/j.leukres.2021.106736. Epub 2021 Oct 28. PMID: 34773794; PMCID: PMC8643322. 6: Shu L, Wang D, Nannapaneni S, Sun Y, Griffith CC, Wang X, Chen Z, Patel M, El-Deiry M, Shin DM, Chen ZG, Saba NF. Tipifarnib enhances anti-EGFR activity of cetuximab in non-HRas mutated head and neck squamous cell carcinoma cancer (HNSCC). Oral Oncol. 2021 Nov;122:105546. doi: 10.1016/j.oraloncology.2021.105546. Epub 2021 Oct 23. PMID: 34700281. 7: Muus P, Langemeijer S, van Bijnen S, Blijlevens N, de Witte T. A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia. Leuk Res. 2021 Jun;105:106573. doi: 10.1016/j.leukres.2021.106573. Epub 2021 Mar 31. PMID: 33915463. 8: Martinez de la Cruz P, Shabaka A, Mielgo-Rubio X, Guerrero-Marquez C, Gimenez-Moyano S, Fernandez-Juarez G. Concomitant Acute Tubular Necrosis and Acute Interstitial Nephritis Induced by Tipifarnib in a Patient with Squamous Cell Carcinoma of the Lung. Am J Med Sci. 2021 Jul;362(1):99-102. doi: 10.1016/j.amjms.2021.04.003. Epub 2021 Apr 16. PMID: 33872582. 9: Egawa N, Tanaka T, Matsufuji S, Yamada K, Ito K, Kitagawa H, Okuyama K, Kitajima Y, Noshiro H. Antitumor effects of low-dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF-1α-expressing gastric cancer cells. FEBS Open Bio. 2021 May;11(5):1465-1475. doi: 10.1002/2211-5463.13154. Epub 2021 Apr 8. PMID: 33773069; PMCID: PMC8091580. 10: Ho AL, Brana I, Haddad R, Bauman J, Bible K, Oosting S, Wong DJ, Ahn MJ, Boni V, Even C, Fayette J, Flor MJ, Harrington K, Kim SB, Licitra L, Nixon I, Saba NF, Hackenberg S, Specenier P, Worden F, Balsara B, Leoni M, Martell B, Scholz C, Gualberto A. Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations. J Clin Oncol. 2021 Jun 10;39(17):1856-1864. doi: 10.1200/JCO.20.02903. Epub 2021 Mar 22. Erratum in: J Clin Oncol. 2021 Oct 1;39(28):3192. PMID: 33750196; PMCID: PMC8189627. 11: Xu XT, Chen J, Ren X, Ma YR, Wang X, Ma YY, Zhao DG, Zhou RP, Zhang K, Goodin S, Li DL, Zheng X. Effects of atorvastatin in combination with celecoxib and tipifarnib on proliferation and apoptosis in pancreatic cancer sphere- forming cells. Eur J Pharmacol. 2021 Feb 15;893:173840. doi: 10.1016/j.ejphar.2020.173840. Epub 2020 Dec 24. PMID: 33359649. 12: Gilardi M, Wang Z, Proietto M, Chillà A, Calleja-Valera JL, Goto Y, Vanoni M, Janes MR, Mikulski Z, Gualberto A, Molinolo AA, Ferrara N, Gutkind JS, Burrows F. Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas. Mol Cancer Ther. 2020 Sep;19(9):1784-1796. doi: 10.1158/1535-7163.MCT-19-0958. Epub 2020 Jul 29. PMID: 32727882; PMCID: PMC7484242. 13: Lee HW, Sa JK, Gualberto A, Scholz C, Sung HH, Jeong BC, Choi HY, Kwon GY, Park SH. A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations. Clin Cancer Res. 2020 Oct 1;26(19):5113-5119. doi: 10.1158/1078-0432.CCR-20-1246. Epub 2020 Jul 7. PMID: 32636318. 14: Hanna GJ, Guenette JP, Chau NG, Sayehli CM, Wilhelm C, Metcalf R, Wong DJ, Brose M, Razaq M, Pérez-Ruiz E, Cohen EEW, Aggarwal R, Scholz C, Gualberto A, Ho AL. Tipifarnib in recurrent, metastatic HRAS-mutant salivary gland cancer. Cancer. 2020 Sep 1;126(17):3972-3981. doi: 10.1002/cncr.33036. Epub 2020 Jun 18. PMID: 32557577; PMCID: PMC8266417. 15: Alonso-Alonso R, Mondéjar R, Martínez N, García-Diaz N, Pérez C, Merino D, Rodríguez M, Esteve-Codina A, Fuste B, Gut M, Burrows F, Scholz C, Vaqué JP, Gualberto A, Piris MÁ. Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma. Sci Rep. 2020 Apr 21;10(1):6721. doi: 10.1038/s41598-020-63434-5. PMID: 32317694; PMCID: PMC7174413. 16: Guo J, Shirozu K, Akahoshi T, Mizuta Y, Murata M, Yamaura K. The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A. Int Immunopharmacol. 2020 Jun;83:106462. doi: 10.1016/j.intimp.2020.106462. Epub 2020 Apr 3. PMID: 32251961. 17: Jazieh K, Molina J, Allred J, Yin J, Reid J, Goetz M, Lim VS, Kaufmann SH, Adjei A. A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors. Invest New Drugs. 2019 Apr;37(2):307-314. doi: 10.1007/s10637-018-0662-1. Epub 2018 Aug 31. PMID: 30171497; PMCID: PMC9594493. 18: Untch BR, Dos Anjos V, Garcia-Rendueles MER, Knauf JA, Krishnamoorthy GP, Saqcena M, Bhanot UK, Socci ND, Ho AL, Ghossein R, Fagin JA. Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. Cancer Res. 2018 Aug 15;78(16):4642-4657. doi: 10.1158/0008-5472.CAN-17-1925. Epub 2018 May 14. PMID: 29760048; PMCID: PMC6095730. 19: Yam C, Murthy RK, Valero V, Szklaruk J, Shroff GS, Stalzer CJ, Buzdar AU, Murray JL, Yang W, Hortobagyi GN, Moulder SL, Arun B. A phase II study of tipifarnib and gemcitabine in metastatic breast cancer. Invest New Drugs. 2018 Apr;36(2):299-306. doi: 10.1007/s10637-018-0564-2. Epub 2018 Jan 27. PMID: 29374384. 20: Nghiemphu PL, Ebiana VA, Wen P, Gilbert M, Abrey LE, Lieberman F, DeAngelis LM, Robins HI, Yung WKA, Chang S, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados M, Kuhn J, Cloughesy TF. Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02. J Neurooncol. 2018 Jan;136(1):79-86. doi: 10.1007/s11060-017-2624-4. Epub 2017 Oct 7. PMID: 28988377; PMCID: PMC5756101.