Farnesyltransferase inhibitor

Studies have suggested that interference with certain post-translational modification processes seem to have quite a high selectivity for targeting cells displaying tumour phenotypes, although the reason for this is a matter of controversy.

Also, a related enzyme geranylgeranyltransferase I (GGTase I) has the ability to transfer a geranylgeranyl group to K and N-Ras (the implications of this are discussed below).

[1] After a program of high-throughput screening of a class of drugs targeting the first step, the farnesyltransferase inhibitors (FTIs) were developed.

It has been suggested that the preclinical successes showing that many N- or K-Ras transformed cell lines (and even tumor cell lines that do not harbor Ras mutations) are sensitive to FTase inhibitors due to inhibition of farnesylation of a number of other proteins.

The mechanism by which FTIs work is through inhibition of this enzyme, which adds a fatty acid molecule to proteins (such as the oncogene, or cancer-generating, ras).

Lets hope for continued success for Link Medicine, so that it will be safe and the lead molecule progresses to the stage of being tested in HD subjects.

[4] FTIs can also be used to inhibit farnesylation in parasites[5] such as Trypanosoma brucei (African sleeping sickness) and Plasmodium falciparum (malaria).

Studies have been published indicating that farnesyltransferase inhibitors such as lonafarnib a synthetic tricyclic derivative of carboxamide with antineoplastic properties can reverse instability of nuclear structure due to the genetic mutation of the LMNA gene.

[6] Results of the first-ever clinical drug trial for children with progeria, demonstrated the efficacy of a farnesyltransferase inhibitor (FTI).

Skeletal formula of tipifarnib (R115777), a farnesyltransferase inhibitor that reached Phase III clinical trials
Untreated cells from children with the genetic disease progeria (left) compared to similar cells treated with farnesyltransferase inhibitors (FTIs). In vitro, FTIs reverse the nuclear damage caused by the disease.
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, x 40)