JMV641 - A POTENT BOMBESIN RECEPTOR ANTAGONIST THAT INHIBITS SWISS 3T3 CELL-PROLIFERATION

The peptides of the bombesin family are involved in stimulation of mit ogenesis in various cell lines, including cancerous cell lines. Bombes in receptor antagonists are of great interest to inhibit this prolifer ation. We have synthesized a potent bombesin receptor antagonist, e.g. , compound JMV641 Gly-His-NH-CH[CH2-CH(CH3)(2)]-**CHOH-(CH2)(3)-CH3 [ (S); **92% of (S) isomer], in which a pseudopeptide bond mimicking th e transition state analogue replaced the peptide bond between the two C-terminal residues. This compound was highly potent to dose-dependent ly inhibit binding of I-125-GRP to Swiss 3T3 cells (IC50 = 0.85 +/- 0. 15 nM) and bombesin-stimulated Swiss 3T3 proliferation (pA(2) = 8.78). However, compound JMV641 can inhibit bombesin-induced AP-1 regulated genes that are nuclear messengers mediating the actions of signal tran sduction pathways stimulated by growth factors.