| 词条 | Tipifarnib |
| 释义 |
| 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 = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = Investigational | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 192185-72-1 | ATC_prefix = None | ATC_suffix = | ATC_supplemental = | 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,[1]{{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.[2] HistoryThe 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] InvestigationsCancerThe 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] ProgeriaIt 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] {{clear left}}References1. ^{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 46 | url = http://www.who.int/medicines/publications/druginformation/innlists/RL46.pdf | publisher = World Health Organization | accessdate = 16 November 2016}} {{Chemotherapeutic agents}}2. ^{{cite journal |last1=Cox |first1=Adrienne D. |last2=Der |first2=Channing J. |last3=Philips |first3=Mark R. |title=Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery? |journal=Clinical Cancer Research |date=15 April 2015 |volume=21 |issue=8 |page=1821 |doi=10.1158/1078-0432.CCR-14-3214 |url=https://doi.org/10.1158/1078-0432.ccr-14-3214 |language=en |issn=1078-0432}} 3. ^"R115777 in Treating Patients With Advanced Solid Tumors" 4. ^"R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas" 5. ^{{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 | accessdate = 16 November 2016 | agency = PR Newswire | date = Jun 30, 2005}} 6. ^{{cite web |last1=Carroll |first1=John |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}} 7. ^{{cite journal |last1=Witzig |first1=Thomas E. |last2=Tang |first2=Hui |last3=Micallef |first3=Ivana N. M. |last4=Ansell |first4=Stephen M. |last5=Link |first5=Brian K. |last6=Inwards |first6=David J. |last7=Porrata |first7=Luis F. |last8=Johnston |first8=Patrick B. |last9=Colgan |first9=Joseph P. |last10=Markovic |first10=Svetomir N. |last11=Nowakowski |first11=Grzegorz S. |last12=Thompson |first12=Carrie A. |last13=Allmer |first13=Cristine |last14=Maurer |first14=Matthew J. |last15=Gupta |first15=Mamta |last16=Weiner |first16=George |last17=Hohl |first17=Ray |last18=Kurtin |first18=Paul J. |last19=Ding |first19=Husheng |last20=Loegering |first20=David |last21=Schneider |first21=Paula |last22=Peterson |first22=Kevin |last23=Habermann |first23=Thomas M. |last24=Kaufmann |first24=Scott H. |title=Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas |journal=Blood |date=3 November 2011 |volume=118 |issue=18 |page=4882 |doi=10.1182/blood-2011-02-334904 |url=https://doi.org/10.1182/blood-2011-02-334904 |language=en |issn=0006-4971}} 8. ^{{cite web |title=Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations {{!}} ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT02383927?term=tipifarnib&rank=9 |website=www.clinicaltrials.gov |language=en |date=10 March 2015}} 9. ^{{cite web |title=Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) {{!}} ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT02464228?term=tipifarnib&rank=7 |website=www.clinicaltrials.gov |language=en |date=12 October 2017}} 10. ^{{cite web |title=Tipifarnib in Subjects With Myelodysplastic Syndromes {{!}} ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT02779777?term=tipifarnib&rank=5 |website=www.clinicaltrials.gov |language=en |date=20 May 2016}} 11. ^{{cite web |title=Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML) {{!}} ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT02807272?term=tipifarnib&rank=3 |website=www.clinicaltrials.gov |language=en |date=12 October 2017}} 12. ^{{cite journal | last1 = Sparano | first1 = JA | last2 = Moulder | first2 = S | last3 = Kazi | first3 = A | last4 = Coppola | first4 = D | last5 = Negassa | first5 = A | last6 = Vahdat | first6 = L | last7 = Li | first7 = T | last8 = Pellegrino | first8 = C | last9 = Fineberg | first9 = S | last10 = Munster | first10 = P | last11 = Malafa | first11 = M | last12 = Lee | first12 = D | last13 = Hoschander | first13 = S | last14 = Hopkins | first14 = U | last15 = Hershman | first15 = D | last16 = Wright | first16 = JJ | last17 = Kleer | first17 = C | last18 = Merajver | first18 = S | last19 = Sebti | first19 = SM | title = Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer | journal = Clinical Cancer Research | date = 15 April 2009 | volume = 15 | issue = 8 | pages = 2942–48 | doi = 10.1158/1078-0432.CCR-08-2658 | pmid = 19351752 | url = http://clincancerres.aacrjournals.org/content/clincanres/15/8/2942.full.pdf | accessdate = 16 November 2016 | pmc = 2785076}} 13. ^{{cite journal | last1 = Alsina | first1 = M | last2 = Fonseca | first2 = R | last3 = Wilson | first3 = EF | last4 = Belle | first4 = AN | last5 = Gerbino | first5 = E | last6 = Price-Troska | first6 = T | last7 = Overton | first7 = RM | last8 = Ahmann | first8 = G | last9 = Bruzek | first9 = LM | last10 = Adjei | first10 = AA | last11 = Kaufmann | first11 = SH | last12 = Wright | first12 = JJ | last13 = Sullivan | first13 = D | last14 = Djulbegovic | first14 = B | last15 = Cantor | first15 = AB | last16 = Greipp | first16 = RP | last17 = Dalton | first17 = WS | last18 = Sebti | first18 = SM | 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 | date = 1 May 2004 | volume = 103 | issue = 9 | pages = 3271–7 | doi = 10.1182/blood-2003-08-2764 | pmid = 14726402 | url = http://www.bloodjournal.org/content/bloodjournal/103/9/3271.full.pdf | accessdate = 16 November 2016}} 14. ^{{cite journal | last1 = Capell | first1 = BC | last2 = Olive | first2 = M | last3 = Erdos | first3 = MR | last4 = Cao | first4 = K | last5 = Faddah | first5 = DA | last6 = Tavarez | first6 = UL | last7 = Conneely | first7 = KN | last8 = Qu | first8 = X | last9 = San | first9 = H | last10 = Ganesh | first10 = SK | last11 = Chen | first11 = X | last12 = Avallone | first12 = H | last13 = Kolodgie | first13 = FD | last14 = Virmani | first14 = R | last15 = Nabel | first15 = EG | last16 = Collins | first16 = FS | 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 | date = 6 October 2008 | volume = 105 | issue = 41 | pages = 15902–7 | doi = 10.1073/pnas.0807840105 | pmid = 18838683 | url = http://www.pnas.org/content/105/41/15902.full.pdf | accessdate = 16 November 2016 | pmc = 2562418}} 5 : Farnesyltransferase inhibitors|Imidazoles|2-Quinolones|Experimental drugs|Chloroarenes |
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