In vitro and in vivo evaluation of two rational-designed nonpeptidic farnesyltransferase inhibitors on HT29 human colon cancer cell lines

FTase inhibitors constitute a new class of potential cancer therapeutics, especially in colorectal cancer where K-ras-selective mutations exist and have a role in tumorigenesis. The synthesis and biological evaluation of two nonpeptidic molecules (13 and 16) designed on the basis of a zinc chelator imidazole linked to two aromatic fragments able to fit in the "exit groove" and in the "A(2) binding site" of FTase are described. These molecules are characterized respectively by a flexible phenylmethyl chain and a more constrained scaffold so as to evaluate their respective influences on site recognition. They have been evaluated in vitro and in vivo against human colon cancer cell lines and 13 not only inhibited tumor growth but also showed no toxic effects at the dose used.