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. 2008 Nov 27;51(22):7169-80.
doi: 10.1021/jm8006849.

Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained Smac mimetics as inhibitors of the X-linked inhibitor of apoptosis protein (XIAP)

Haiying Sun  1 , Jeanne A Stuckey, Zaneta Nikolovska-Coleska, Dongguang Qin, Jennifer L Meagher, Su Qiu, Jianfeng Lu, Chao-Yie Yang, Naoyuki G Saito, Shaomeng Wang
Affiliations

Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained Smac mimetics as inhibitors of the X-linked inhibitor of apoptosis protein (XIAP)

Haiying Sun et al. J Med Chem. .

Abstract

Small molecules designed to mimic the binding of Smac protein to X-linked inhibitor of apoptosis protein (XIAP) are being pursued as a promising new class of anticancer drugs. Herein, we report the design, synthesis, and comprehensive structure-activity relationship studies of a series of conformationally constrained bicyclic Smac mimetics. Our studies led to the discovery of a number of highly potent and cell-permeable Smac mimetics and yielded important new insights into their structure-activity relationship for their binding to XIAP and for their activity in inhibition of cancer cell growth. Determination of the crystal structure of one potent Smac mimetic, compound 21, in complex with XIAP BIR3 provides the structural basis for its high-affinity binding to XIAP and for the design of highly potent Smac mimetics.

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Figures

Figure 1
Figure 1
Design and examples of conformationally constrained bicyclic Smac peptide mimetics.
Figure 2
Figure 2
Predicted binding models of compounds 2, 4, 5, 20 and 21 to XIAP BIR3 protein in comparison with that for Smac AVPI peptide in the crystal structure. Carbon atoms in compounds 2, 4, 5, 20 and 21 and AVPI are shown in stick. The carbon atoms are colored in yellow in 2, 4, 5, 20 and 21 and in green in the AVPI peptide. The carbon atoms in several key residues in XIAP are colored in grey. Nitrogen and oxygen atoms are colored in blue and red, respectively.
Figure 3
Figure 3
Functional antagonism of compounds 20, 24, 25, and the AVPI peptide against XIAP BIR3 to promote the activity of caspase-9 in a cell-free functional assay.
Figure 4
Figure 4
Inhibition of cell growth by Smac mimetics in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines. Cells were treated for 4 days and cell growth was determined using WST-based assay.
Figure 5
Figure 5
Induction of apoptosis by Smac mimetics in the human breast cancer MDA-MB-231 cell line. Cells were treated for 48 hours and apoptosis was determined using Annexin V-propidium iodide(P.I.) staining by flow cytometry. Annexin V (+) and P.I. (−) cells are labeled as early apoptotic cells, whereas Annexin V (+) and P.I. (+) cells are labeled as late apoptotic cells. Percentage of early and late apoptotic cells are shown.
Figure 6
Figure 6
Induction of cell death by compounds 20 and 25 in the human breast cancer MDA-MB-231 cell line and dependence on caspase-3/7. Cells were treated with different concentrations of Smac mimetic for 48 hours and cell viability was determined using trypan blue exclusion assay. To determine the dependence of cell death induction by Smac mimetics on caspase-3/-7, a cell-permeable caspase-3/-7 inhibitor, Z-DEVD-FMK, was employed.
Figure 7
Figure 7
X-ray crystal structure of compound 21 in complex with human XIAP BIR3, determined to 2.8 Å resolution. (A). Overall representation of compound 21 in complex with XIAP BIR3. Compound 21 is shown in green ball-n-stick. (B). Detailed interactions between compound 21 and XIAP BIR3 residues shown as a 90° rotation of the yellow domain in A. Compound 21 is shown in yellow ball-n-stick. (C). Superposition of modeled and crystal structures of compound 21 in complex with XIAP BIR3.
Scheme 1
Scheme 1. General synthesis of conformationally constrained [8,5] bicyclic Smac mimetics
Reagents and conditions: (a) i. Amine, EDC, HOBt, N,N-diisopropylethylamine, CH2Cl2, overnight; ii. 4 N HCl in 1,4-dioxane, MeOH; iii. N-Boc-L-aminoacid, EDC, HOBt, N,N-diisopropylethylamine, CH2Cl2; iv. 4 N HCl in 1,4-dioxane, MeOH; (b) 1,4-dibromobutane or 2-bromoethyl ether, N,N-diisopropylethylamine, MeOH, reflux, 67% for 22 and 54% for 23; (c) i. aminodiphenylmethane, EDC, HOBt, N,N-diisopropylethylamine, CH2Cl2, overnight; ii. 4 N HCl in 1,4-dioxane, MeOH; iii. L-lactic acid, EDC, HOBt, N,N-diisopropylethylamine, CH2Cl2, 71% over three steps.
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