Tipifarnib (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, proposed trade name Zarnestra) is a

farnesyltransferase inhibitor 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 ...

. 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.

History

The compound was discovered by

Johnson & Johnson Pharmaceutical Research & Development Johnson & Johnson Pharmaceutical Research and Development (J&JPRD) is a subsidiary of Johnson & Johnson that is responsible for drug discovery, discovering and drug development, developing pharmaceutical drugs. J&JPRD has research sites located in ...

, 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. Tipifarnib was submitted to the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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. Kura Oncology in-licensed tipifarnib from Janssen in 2014.

Investigations

Cancer

The inhibitor is being investigated in patients with HRAS mutant head and neck cancer,

peripheral T-cell lymphoma Peripheral T-cell lymphoma refers to a group of T-cell lymphomas that develop away from the thymus or bone marrow. Examples include: * Cutaneous T-cell lymphomas * Angioimmunoblastic T-cell lymphoma * Extranodal natural killer/T-cell lymphoma, nas ...

(PTCL),

myelodysplastic syndromes A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

(MDS), and

chronic myelomonocytic leukemia Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are i ...

(CMML). It was previously tested in clinical trials in patients in certain stages of breast cancer. It was also investigated as a treatment for multiple myeloma.

Progeria

It was shown on a mouse model of

Hutchinson–Gilford progeria syndrome Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...

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.

References

{{Chemotherapeutic agents Farnesyltransferase inhibitors Imidazoles 2-Quinolones Experimental drugs Chloroarenes Orphan drugs