Tipifarnib (INN,[1]: 213 proposed trade nameZarnestra) is afarnesyltransferase 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 theFDA byJohnson & Johnson for the treatment of AML in patients aged 65 and over with anew 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 ofHutchinson–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]
^Clinical trial numberNCT00029354 for "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas" atClinicalTrials.gov
^Clinical trial numberNCT02383927 for "Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations" atClinicalTrials.gov
^Clinical trial numberNCT02464228 for "Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)" atClinicalTrials.gov
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