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Other namesR115777
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  • Investigational
  • (+)-6-[(R)-Amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one
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Chemical and physical data
Formula C27H22Cl2N4O
Molar mass 489.40 g·mol−1
3D model (JSmol)
  • CN1C(=O)C=C(c2cccc(Cl)c2)c3cc(ccc13)[C@](N)(c4ccc(Cl)cc4)c5cncn5C
  • 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 X mark.svgN
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Tipifarnib (INN, [1] :213 proposed trade name Zarnestra) is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive. [2]



The compound was discovered by Johnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777.

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, it passed phase I clinical trials but was suspended (NCT00029354) in phase II. [3] [4]

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 FDA on January 24, 2005. In June 2005, the FDA issued a "not approvable" letter for tipifarnib. [5]

Kura Oncology in-licensed tipifarnib from Janssen in 2014. [6]



The inhibitor is being investigated in patients with HRAS mutant head and neck cancer, peripheral T-cell lymphoma (PTCL), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML). [7] [8] [9] [10] [11] It was previously tested in clinical trials in patients in certain stages of breast cancer. [12] It was also investigated as a treatment for multiple myeloma. [13]


Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left picture) and the other treated with the farnsyltransferase inhibitor drug tipifarnib (right picture). The microphotographs show prevention of the vascular smooth muscle cell loss that is otherwise rampant by this age. Staining was smooth muscle alpha-actin (green), lamins A/C (red) and DAPI (blue). (Original magnification, x40) Progeria20132-300.jpg
Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left picture) and the other treated with the farnsyltransferase inhibitor drug tipifarnib (right picture). The microphotographs show prevention of the vascular smooth muscle cell loss that is otherwise rampant by this age. Staining was smooth muscle alpha-actin (green), lamins A/C (red) and DAPI (blue). (Original magnification, ×40)

It was shown on a mouse model of Hutchinson–Gilford progeria syndrome that dose-dependent administration of tipifarnib can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. [14]

Related Research Articles

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The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in cancer.

<span class="mw-page-title-main">Neurofibromatosis type I</span> Type of neurofibromatosis disease

Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of Neurofibromin 1, a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.

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<span class="mw-page-title-main">Neurofibroma</span> Medical condition

A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors, while the remainder are found in persons with neurofibromatosis type I (NF1), an autosomal-dominant genetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.

<span class="mw-page-title-main">Costello syndrome</span> Medical condition

Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet. Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle. Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones. It is a RASopathy.

<span class="mw-page-title-main">Neurofibromin 1</span> Mammalian protein found in Homo sapiens

neurofibromatosis 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

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Channing Joseph Der is an American scientist and educator, and Sarah Graham Kenan Distinguished Professor of Pharmacology, at UNC Lineberger Comprehensive Cancer Center. Der is a Fellow of the American Association for the Advancement of Science, He is recognized for his work with the Ras oncoprotein and its role in human oncogenesis.


  1. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 46" (PDF). World Health Organization. Retrieved 16 November 2016.
  2. Cox AD, Der CJ, Philips MR (April 2015). "Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?". Clinical Cancer Research. 21 (8): 1819–27. doi:10.1158/1078-0432.CCR-14-3214. PMC   4400837 . PMID   25878363.
  3. Clinical trial number NCT00025454 for "R115777 in Treating Patients With Advanced Solid Tumors" at ClinicalTrials.gov
  4. Clinical trial number NCT00029354 for "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas" at ClinicalTrials.gov
  5. "Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Receives Not Approvable Letter From FDA for Tipifarnib Based on Phase II Data". PR Newswire. Jun 30, 2005. Retrieved 16 November 2016.
  6. Carroll J (12 March 2015). "Kura sheds stealth mode with $60M for PhII cancer drug licensed from J&J | FierceBiotech". www.fiercebiotech.com.
  7. Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, et al. (November 2011). "Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas". Blood. 118 (18): 4882–9. doi:10.1182/blood-2011-02-334904. PMC   3208296 . PMID   21725056.
  8. Clinical trial number NCT02383927 for "Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations" at ClinicalTrials.gov
  9. Clinical trial number NCT02464228 for "Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)" at ClinicalTrials.gov
  10. Clinical trial number NCT02779777 for "Tipifarnib in Subjects With Myelodysplastic Syndromes" at ClinicalTrials.gov
  11. Clinical trial number NCT02807272 for "Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
  12. Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, et al. (April 2009). "Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer". Clinical Cancer Research. 15 (8): 2942–8. doi:10.1158/1078-0432.CCR-08-2658. PMC   2785076 . PMID   19351752.
  13. Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T, et al. (May 2004). "Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma". Blood. 103 (9): 3271–7. doi: 10.1182/blood-2003-08-2764 . PMID   14726402.
  14. Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, et al. (October 2008). "A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 105 (41): 15902–7. Bibcode:2008PNAS..10515902C. doi: 10.1073/pnas.0807840105 . PMC   2562418 . PMID   18838683.