More than a decade ago we developed a highly potent bradykinin (BK) antagonist peptide dimer with excellent anticancer activity against small cell lung cancer (SCLC) (B9870; DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg, Hyp: toms-4-hydroxyproline; Igl: a-(2-mdanyl)glycine; Oic: octahydroindole-2-carboxylic acid; GPI: 8.4 (pA2 for BK antagonist activity on isolated guinea pig ileum); SHP-77: 65% (percent inhibition on growth of xenografts in nude mice, compound was injected i.p. at 5 mg/kg/day for 27 days) [1]. The transformation of our B9870 BK anticancer peptide dimer into peptidomimetics led us to the discovery of BKM570, a small molecule with highly potent anticancer activity (SHP-77: 91%), but moderate BK antagonist activity (GPI: 5.6) [1]. This first generation of our small molecules was found to be superior to the widely used but highly toxic cisplatin against SCLC in vivo and also showed strong cytotoxic effects in ovarian cancer cells [2]. This simple N-acyl-tyrosine-amide derivative BKM570 (Figure 1), which was chosen for further optimization studies, consists of subunits "A" acyl-group: pentafluorocinnamoyl, "B" amino acid residue 0-(2,6-dichlorobenzyl)tyrosine and "C" stoically hindered cyclic amide derivative: 4-amino-2,2,6,6-tetramethylpiperidine.
展开▼
