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1.  A potent and orally active antagonist of multiple inhibitor of apoptosis proteins (IAPs) (SM-406/AT-406) in clinical development for cancer treatment 
Journal of medicinal chemistry  2011;54(8):2714-2726.
We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.
doi:10.1021/jm101505d
PMCID: PMC3520070  PMID: 21443232
2.  Potent Bivalent Smac Mimetics: Effect of the Linker on Binding to Inhibitor of Apoptosis Proteins (IAPs) and Anticancer Activity 
Journal of medicinal chemistry  2011;54(9):3306-3318.
We have synthesized and evaluated a series of non-peptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultra-potent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC50 values from 1–3 nM in the MDA-MB-231 breast cancer cell line and are 100-times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations, hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts, while causing no signs of toxicity in the animals.
doi:10.1021/jm101651b
PMCID: PMC3108148  PMID: 21462933
3.  Non-peptidic and Potent Small-Molecule Inhibitors of cIAP-1/2 and XIAP Proteins 
Journal of medicinal chemistry  2010;53(17):6361-6367.
A series of compounds were designed and synthesized as antagonists of cIAP-1/2 and XIAP based upon our previously identified lead compound SM-122 (1). The most potent of these (7) binds to XIAP, cIAP-1 and cIAP-2 proteins with Ki values of 36, <1 and <1.9 nM, respectively. Consistent with its potent binding affinities to IAPs, 7 effectively antagonizes XIAP in a cell-free caspase-9 functional assay, efficiently induces cIAP-1 degradation in cells at concentrations as low as 10 nM, and triggers activation of caspases and PARP cleavage in the MDA-MB-231 breast cancer cell line. Compound 7 potently inhibits cell growth in the MDA-MB-231 cancer cell line with an IC50 value of 200 nM and is 9 times more potent than compound 1.
doi:10.1021/jm100487z
PMCID: PMC2936695  PMID: 20684551
4.  Potent and Orally Active Small-Molecule Inhibitors of the MDM2-p53 Interaction 
Journal of medicinal chemistry  2009;52(24):7970-7973.
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a Ki value of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
doi:10.1021/jm901400z
PMCID: PMC2795799  PMID: 19928922
5.  Design, Synthesis and Evaluation of Potent, Non-Peptidic Mimetics of Second Mitochondria-derived Activator of Caspases 
Journal of medicinal chemistry  2009;52(3):593-596.
A series of new Smac mimetics have been designed, synthesized and evaluated. The most potent compound 10 binds to XIAP, cIAP-1 and cIAP-2 BIR3 proteins with Ki values of 3.9, 0.37 and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC50 value of 8.9 nM.
doi:10.1021/jm801101z
PMCID: PMC2795317  PMID: 19138149
6.  Potent, Orally Bioavailable Diazabicyclic Small-Molecule Mimetics of Second Mitochondria-derived Activator of Caspases 
Journal of medicinal chemistry  2008;51(24):8158-8162.
A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized and evaluated. The most potent compound (6) binds to XIAP, cIAP-1 and cIAP-2 with Ki values of 8.4, 1.5 and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line and has a good oral bioavailability.
doi:10.1021/jm801254r
PMCID: PMC2679375  PMID: 19049347
7.  Design, Synthesis and Evaluation of Tricyclic, Conformationally Constrained Small-Molecule Mimetics of Second Mitochondria-derived Activator of Caspases 
Journal of medicinal chemistry  2008;51(23):7352-7355.
A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1 and cIAP-2 with Ki values of 18, 1.1 and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay and induces cIAP-1 degradation. Compound 6 inhibits cell growth with an IC50 value of 68 nM in the MDA-MB-231 cancer cell line and effectively induces cancer cells to undergo apoptosis.
doi:10.1021/jm801146d
PMCID: PMC2662380  PMID: 19012392
8.  Structure-Based Design, Synthesis, Evaluation and Crystallographic Studies of Conformationally Constrained Smac Mimetics as Inhibitors of the X-linked Inhibitor of Apoptosis Protein (XIAP)∞ 
Journal of medicinal chemistry  2008;51(22):7169-7180.
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.
doi:10.1021/jm8006849
PMCID: PMC2688463  PMID: 18954041
10.  Structure-Based Design of Flavonoid Compounds As a New Class of Small-Molecule Inhibitors of the Anti-apoptotic Bcl-2 Proteinŝ 
Journal of medicinal chemistry  2007;50(14):3163-3166.
Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-231 breast cancer cell line with an IC50 value of 110 nM and effectively induces apoptosis.
doi:10.1021/jm070383c
PMCID: PMC2527594  PMID: 17552510

Results 1-10 (10)