tipifarnib
{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 376279232
| IUPAC_name = (+)-6-[(R)-Amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one
| image = Tipifarnib.svg
| tradename =
| pregnancy_AU =
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| legal_US =
| legal_status = Investigational
| routes_of_administration =
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| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 192185-72-1
| ATC_prefix = None
| ATC_suffix =
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| PubChem = 159324
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB04960
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 140122
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = MAT637500A
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D03720
| ChEBI = 141969
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 289228
| IUPHAR_ligand = 8025
| C=27 | H=22 | Cl=2 | N=4 | O=1
| molecular_weight =
| smiles = CN1C(=O)C=C(c2cccc(Cl)c2)c3cc(ccc13)[C@](N)(c4ccc(Cl)cc4)c5cncn5C
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = PLHJCIYEEKOWNM-HHHXNRCGSA-N
| synonyms = R115777
}}
Tipifarnib (INN,{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 46 | url =https://www.who.int/medicines/publications/druginformation/innlists/RL46.pdf | publisher = World Health Organization | access-date = 16 November 2016}}{{rp|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.{{cite journal | vauthors = Cox AD, Der CJ, Philips MR | title = Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery? | journal = Clinical Cancer Research | volume = 21 | issue = 8 | pages = 1819–27 | date = April 2015 | pmid = 25878363 | pmc = 4400837 | doi = 10.1158/1078-0432.CCR-14-3214 }}
History
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.{{ClinicalTrialsGov|NCT00025454|R115777 in Treating Patients With Advanced Solid Tumors}}{{ClinicalTrialsGov|NCT00029354|R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas}}
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.{{cite news | title = Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Receives Not Approvable Letter From FDA for Tipifarnib Based on Phase II Data | url = http://www.prnewswire.com/news-releases/johnson--johnson-pharmaceutical-research--development-llc-receives-not-approvable-letter-from-fda-for-tipifarnib-based-on-phase-ii-data-54993352.html | access-date = 16 November 2016 | agency = PR Newswire | date = Jun 30, 2005}}
Kura Oncology in-licensed tipifarnib from Janssen in 2014.{{cite web |last1=Carroll |first1=John | name-list-style = vanc |title=Kura sheds stealth mode with $60M for PhII cancer drug licensed from J&J {{!}} FierceBiotech |url=https://www.fiercebiotech.com/r-d/kura-sheds-stealth-mode-60m-for-phii-cancer-drug-licensed-from-j-j |website=www.fiercebiotech.com |language=en |date=12 March 2015}}
Investigations
=Cancer=
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).{{cite journal | vauthors = Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, Porrata LF, Johnston PB, Colgan JP, Markovic SN, Nowakowski GS, Thompson CA, Allmer C, Maurer MJ, Gupta M, Weiner G, Hohl R, Kurtin PJ, Ding H, Loegering D, Schneider P, Peterson K, Habermann TM, Kaufmann SH | display-authors = 6 | title = Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas | journal = Blood | volume = 118 | issue = 18 | pages = 4882–9 | date = November 2011 | pmid = 21725056 | pmc = 3208296 | doi = 10.1182/blood-2011-02-334904 }}{{ClinicalTrialsGov|NCT02383927|Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations}}{{ClinicalTrialsGov|NCT02464228|Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)}}{{ClinicalTrialsGov|NCT02779777|Tipifarnib in Subjects With Myelodysplastic Syndromes}}{{ClinicalTrialsGov|NCT02807272|Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML)}} It was previously tested in clinical trials in patients in certain stages of breast cancer.{{cite journal | vauthors = Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, Li T, Pellegrino C, Fineberg S, Munster P, Malafa M, Lee D, Hoschander S, Hopkins U, Hershman D, Wright JJ, Kleer C, Merajver S, Sebti SM | display-authors = 6 | title = Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer | journal = Clinical Cancer Research | volume = 15 | issue = 8 | pages = 2942–8 | date = April 2009 | pmid = 19351752 | pmc = 2785076 | doi = 10.1158/1078-0432.CCR-08-2658 | url = }} It was also investigated as a treatment for multiple myeloma.{{cite journal | vauthors = Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T, Overton RM, Ahmann G, Bruzek LM, Adjei AA, Kaufmann SH, Wright JJ, Sullivan D, Djulbegovic B, Cantor AB, Greipp PR, Dalton WS, Sebti SM | display-authors = 6 | title = Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma | journal = Blood | volume = 103 | issue = 9 | pages = 3271–7 | date = May 2004 | pmid = 14726402 | doi = 10.1182/blood-2003-08-2764 | doi-access = free }}
=Progeria=
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.{{cite journal | vauthors = Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, Conneely KN, Qu X, San H, Ganesh SK, Chen X, Avallone H, Kolodgie FD, Virmani R, Nabel EG, Collins FS | display-authors = 6 | title = A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 41 | pages = 15902–7 | date = October 2008 | pmid = 18838683 | pmc = 2562418 | doi = 10.1073/pnas.0807840105 | url = http://www.pnas.org/content/105/41/15902.full.pdf | bibcode = 2008PNAS..10515902C | doi-access = free }}
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