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]
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]
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]
Referencesedit
^"International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 46" (PDF). World Health Organization. Retrieved 16 November 2016.
^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. PMC4400837. PMID 25878363.
^Clinical trial number NCT00025454 for "R115777 in Treating Patients With Advanced Solid Tumors" at ClinicalTrials.gov
^Clinical trial number NCT00029354 for "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas" at ClinicalTrials.gov
^"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.
^Carroll J (12 March 2015). "Kura sheds stealth mode with $60M for PhII cancer drug licensed from J&J | FierceBiotech". www.fiercebiotech.com.
^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. PMC3208296. PMID 21725056.
^Clinical trial number NCT02383927 for "Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations" at ClinicalTrials.gov
^Clinical trial number NCT02464228 for "Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)" at ClinicalTrials.gov
^Clinical trial number NCT02779777 for "Tipifarnib in Subjects With Myelodysplastic Syndromes" at ClinicalTrials.gov
^Clinical trial number NCT02807272 for "Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
^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. PMC2785076. PMID 19351752.
^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.
^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. PMC2562418. PMID 18838683.
December 15, 2023
tipifarnib, proposed, trade, name, zarnestra, farnesyltransferase, inhibitor, farnesyltransferase, inhibitors, block, activity, farnesyltransferase, enzyme, inhibiting, prenylation, caax, tail, motif, which, ultimately, prevents, from, binding, membrane, rende. 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 TipifarnibClinical dataOther namesR115777ATC codeNoneLegal statusLegal statusInvestigationalIdentifiersIUPAC name 6 R Amino 4 chlorophenyl 3 methylimidazol 4 yl methyl 4 3 chlorophenyl 1 methylquinolin 2 oneCAS Number192185 72 1 NPubChem CID159324IUPHAR BPS8025DrugBankDB04960 NChemSpider140122 NUNIIMAT637500AKEGGD03720 NChEBICHEBI 141969ChEMBLChEMBL289228 NCompTox Dashboard EPA DTXSID5041140Chemical and physical dataFormulaC 27H 22Cl 2N 4OMolar mass489 40 g mol 13D model JSmol Interactive imageSMILES CN1C O C C c2cccc Cl c2 c3cc ccc13 C N c4ccc Cl cc4 c5cncn5CInChI 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 NKey PLHJCIYEEKOWNM HHHXNRCGSA N N N Y what is this verify Contents 1 History 2 Investigations 2 1 Cancer 2 2 Progeria 3 ReferencesHistory editThe compound was discovered by Johnson amp Johnson Pharmaceutical Research amp 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 amp 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 Investigations editCancer edit 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 Progeria edit nbsp 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 References edit International Nonproprietary Names for Pharmaceutical Substances INN Recommended International Nonproprietary Names Rec INN List 46 PDF World Health Organization Retrieved 16 November 2016 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 Clinical trial number NCT00025454 for R115777 in Treating Patients With Advanced Solid Tumors at ClinicalTrials gov Clinical trial number NCT00029354 for R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas at ClinicalTrials gov Johnson amp Johnson Pharmaceutical Research amp 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 Carroll J 12 March 2015 Kura sheds stealth mode with 60M for PhII cancer drug licensed from J amp J FierceBiotech www fiercebiotech com 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 Clinical trial number NCT02383927 for Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations at ClinicalTrials gov Clinical trial number NCT02464228 for Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T Cell Lymphoma PTCL at ClinicalTrials gov Clinical trial number NCT02779777 for Tipifarnib in Subjects With Myelodysplastic Syndromes at ClinicalTrials gov Clinical trial number NCT02807272 for Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia CMML at ClinicalTrials gov 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 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 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 Retrieved from https en wikipedia org w index php title Tipifarnib amp oldid 1187851992, wikipedia, wiki, book, books, library,
