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1.  A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor 
Journal of medicinal chemistry  2013;56(7):3048-3067.
Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with Ki values of < 1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete and durable tumor regression in vivo at a well-tolerated dose-schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
doi:10.1021/jm4001105
PMCID: PMC3806060  PMID: 23448298
2.  Structure-Based Discovery of BM-957 as a Potent Small-Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving Complete Tumor Regression 
Journal of medicinal chemistry  2012;55(19):8502-8514.
Bcl-2 and Bcl-xL anti-apoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with Ki <1 nM and has low nanomolar IC50 values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose-schedule.
doi:10.1021/jm3010306
PMCID: PMC3495162  PMID: 23030453
3.  Structure-based Design of Potent Bcl-2/Bcl-xL Inhibitors with Strong in vivo Antitumor Activity 
Journal of medicinal chemistry  2012;55(13):6149-6161.
Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar Ki values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC50 values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
doi:10.1021/jm300608w
PMCID: PMC3417242  PMID: 22747598
4.  Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based Upon a New Scaffold 
Journal of Medicinal Chemistry  2012;55(10):4664-4682.
Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and FDA-approved drugs and was found to have an affinity of 100 μM to both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10,000. Further optimization ultimately yielded compounds with subnanomolar binding affinities to both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with Ki < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC50 values of 60–90 nM and induces robust cell death in the H146 cancer cell line at 30–100 nM.
doi:10.1021/jm300178u
PMCID: PMC3397176  PMID: 22448988
5.  Design of Triazole-stapled BCL9 α-Helical Peptides to Target the β-Catenin/B-cell CLL/lymphoma 9 (BCL9) Protein-Protein Interaction 
Journal of Medicinal Chemistry  2012;55(3):1137-1146.
The interaction between β-catenin and B-cell CLL/lymphoma 9 (BCL9), critical for the transcriptional activity of β-catenin, is mediated by a helical segment from BCL9 and a large binding groove in β-catenin. Design of potent, metabolically stable BCL9 peptides represents an attractive approach to inhibit the activity of β-catenin. In this study, we report the use of the Huisgen 1,3-dipolar cycloaddition reaction to generate triazole-stapled BCL9 α-helical peptides. The high efficiency and mild conditions of this “click” reaction combined with the ease of synthesis of the necessary unnatural amino acids allows for facile synthesis of triazole-stapled peptides. We have performed extensive optimization of this approach and identified the optimal combinations of azido and alkynyl linkers necessary for stapling BCL9 helices. The unsymmetrical nature of the triazole staple also allowed the synthesis of double-stapled BCL9 peptides, which show a marked increase in helical character and an improvement in binding affinity and metabolic stability relative to wild-type and linear BCL9 peptides. This study lays the foundation for further optimization of these triazole-stapled BCL9 peptides as potent, metabolically stable and cell-permeable inhibitors to target the β-catenin and BCL9 interaction.
doi:10.1021/jm201125d
PMCID: PMC3286869  PMID: 22196480
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Design, Synthesis and Evaluation of Potent and Selective Ligands for the Dopamine 3 (D3) Receptor with a Novel in vivo Behavioral Profile 
Journal of medicinal chemistry  2008;51(19):5905-5908.
A series of compounds structurally related to pramipexole were designed, synthesized and evaluated as ligands for the dopamine 3 (D3) receptor. Compound 12 has a Ki value of 0.41 nM to D3 and a selectivity of >30,000- and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor.
doi:10.1021/jm800471h
PMCID: PMC2662387  PMID: 18785726
14.  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 1-14 (14)