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Wehave designed, synthesized, and evaluated a series of new compoundsbased upon our previously reported bivalent Smac mimetics. This ledto the identification of compound 12(SM-1200), whichbinds to XIAP, cIAP1, and cIAP2 with Kivalues of 0.5, 3.7, and 5.4 nM, respectively, inhibits cell growthin the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lineswith IC50values of 11.0 and 28.2 nM, respectively. Compound 12has a much improved pharmacokinetic profile over our previouslyreported bivalent Smac mimetics and is highly effective in inductionof rapid and durable tumor regression in the MDA-MB-231 xenograftmodel. These data indicate that compound 12is a promisingSmac mimetic and warrants extensive evaluation as a potential candidatefor clinical development. [ABSTRACT FROM AUTHOR]

Without the presence of a phosphotyrosyl group, a phage library derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain attributed its high affinity and specificity to well-defined and highly favored interactions of its structural elements with the binding pocket of the protein. We have disclosed a significant compensatory role of the Glu2− sidechain for the absence of the phosphate functionality on Tyr0 in the peptide ligand, cyclo(CH2CO-Glu2−-Leu-Tyr0-Glu-Asn-Val-Gly-Met5+-Tyr-Cys)-amide (termed G1TE). In this study, we report the importance of hydrophobic residue at the Tyr + 5 site in G1TE. Both acidic and basic amino acid substitutes are disfavored at this position, and replacement of Met with β-tert-butyl-Ala was found to improve the antagonist properties. Besides, the polarity of the cyclization linkage was implicated as important in stabilizing the favored binding conformation. Oxidation of the thioether linkage into sulfoxide facilitated the binding to Grb2-SH2 markedly. Simultaneous modification of the three distant sites within G1TE provided the best agent with an IC50 of 220 nM, which is among the most potent non-phosphorous- and non-phosphotyrosine-mimic containing Grb2-SH2 domain inhibitors yet reported. This potent peptidomimetic provides a novel template for the development of chemotherapeutic agents for the treatment of erbB2-related cancer. Biological assays on G1TE(Gla2−) in which the original residue of Glu2− was substituted by γ-carboxyglutamic acid (Gla) indicated that it could inhibit the interaction between activated GF receptor and Grb2 protein in cell homogenates of MDA-MB-453 breast cancer cells at the 2 μM level. More significantly, both G1TE(Gla2−) alone and the conjugate of G1TE(Gla2−) with a peptide carrier can effectively inhibit intracellular association of erbB2 and Grb2 in the same cell lines with IC50 of 50 and 2 μM, respectively. [Copyright &y& Elsevier]