Synthesis and structure–activity relationships of novel benzofuran farnesyltransferase inhibitors

Tipifarnib-Induced Apoptosis in Acute Myeloid Leukemia and Multiple Myeloma Cells Depends on Ca2+Influx through Plasma Membrane Ca2+Channels

“…Previous studies, including our own, have demonstrated the anticancer activity of tipifarnib as a single agent or in combination in preclinical models for multiple myeloma and acute myeloid leukemia (Alsina et al, 2004;Beaupre et al, 2004;Yanamandra et al, 2006). However, a study in which modifications were made to the core structure of tipifarnib to generate novel benzofuran FTIs showed that the antiproliferative properties of the tipifarnib analogs were not exclusively related to their affinity for farnesyltransferase (Asoh et al, 2009). Some compounds with high FTI activity exhibited little antiproliferative effects, suggesting that FTI activity is not sufficient to inhibit cancer cell growth (Asoh et al, 2009).…”

“…However, a study in which modifications were made to the core structure of tipifarnib to generate novel benzofuran FTIs showed that the antiproliferative properties of the tipifarnib analogs were not exclusively related to their affinity for farnesyltransferase (Asoh et al, 2009). Some compounds with high FTI activity exhibited little antiproliferative effects, suggesting that FTI activity is not sufficient to inhibit cancer cell growth (Asoh et al, 2009). Thus, the molecular mechanisms by which tipifarnib triggers cell death still remain elusive and have not been unequivocally associated with farnesyltransferase inhibition.…”

In Silico–Based Structural Analysis of Arylthiophene Derivatives for FTase Inhibitory Activity, hERG, and Other Toxic Effects

“…in fact, the two available X-ray crystallographic structures along with benzofuran molecules (PdB codes 2Zir and 2Zis) show the existence of particularly short Zn-n bond lengths between benzofuran derivatives and the catalytically relevant Zn(ii) metal ion in the ftase active site. 29 the important role of this amino acid residue (lys164α, arg291β, and lys294β) for molecule binding to the ftase active site has been previously demonstrated in structural and mutagenesis studies 30 and was the subject of particular attention in some of our molecular dynamics studies, 9 suggesting that against natural peptidic caaX substrates, this residue establishes an important interaction with the negatively charged terminal carboxylate group and makes a very important contribution to enzyme substrate affinity. in addition to this amino acid residue, several other positively charged amino acid residues have been previously implicated in substrate/inhibitor binding.…”

“…in addition to this amino acid residue, several other positively charged amino acid residues have been previously implicated in substrate/inhibitor binding. 29,30 this suggests that the negatively charged groups on the vdW surface of the molecule are important for interaction with the Zn 2+ ion and other positively charged amino acid residues in the active site.…”

Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors

“…A series of novel benzofuran derivatives, for which the FTase inhibitory activity and the antiproliferative activity on human non-small cell lung carcinoma (QG56) has been recently described in the literature 38 was considered to perform the QSAR study. This series was based on tipifarnib (R115777 8 ), one of the most potent FTase inhibitors currently undergoing clinical trials, with a novel benzofuran core template replacing the quinolinone moiety of tipifarnib 38 .…”