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1.  A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells 
Journal of Medicinal Chemistry  2012;55(5):2427-2436.
The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells.
PMCID: PMC3299084  PMID: 22329578
2.  Design and characterization of a potent and selective dual ATP- and substrate-competitive sub-nanomolar bi-dentate c-Jun N-terminal Kinase (JNK) inhibitor 
Journal of medicinal chemistry  2011;54(18):6206-6214.
c-Jun N-terminal Kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bi-dentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bi-dentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC50 = 18 nM; Ki = 1.5 nM) and JNK/substrate association in a displacement assay with a substrate peptide (compound 20; IC50 = 46 nM; Ki = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 not only inhibits JNK in a variety of cell-based experiments, but it elicits also in vivo activity where it is shown to improve glucose tolerance in diabetic mice.
PMCID: PMC3174326  PMID: 21815634
3.  SAR by Inter-Ligand nuclear Overhauser Effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-xL and Mcl-1 
Journal of medicinal chemistry  2011;54(17):6000-6013.
Over expression of anti-apoptotic members of the Bcl-2 family proteins, such as Bcl-xL and Mfl-1 has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted in the development of the acylsulfonamide compound and clinical candidate that targets selectively Bcl-2, Bcl-xL and Bcl-w while is not active against Mcl-1 and Bfl-1. However, early clinical and pre-clinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL and possibly all other four anti-apoptotic Bcl-2 proteins, may result in more efficacious drugs. Here, following an NMR fragment-based approach, SAR by ILOEs, we report on compounds that exhibit nanomolar affinities for both BclxL and Mcl-1 in vitro. We believe that these molecules can be used as useful starting point for the development of novel Bcl-2 antagonists, in particular targeting Mcl-1.
PMCID: PMC3165075  PMID: 21797225
4.  Design, synthesis, and structure-activity relationships of 3-ethynyl-1H-indazoles as inhibitors of Phosphatidylinositol 3-kinase signaling pathway 
Journal of medicinal chemistry  2010;53(23):8368-8375.
A new series of 3-ethynyl-1H–indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1 and mTOR kinases. Combination of computational modeling and structure-activity relationships studies reveal a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays anti-proliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could result useful in deriving novel selecting and multi-kinase inhibitors for clinical use.
PMCID: PMC3131451  PMID: 21062009
5.  Synthesis and Biological Evaluation of Apogossypolone Derivatives as Pan-active Inhibitors of Anti-apoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins 
Journal of medicinal chemistry  2010;53(22):8000-8011.
Overexpression of anti-apoptotic Bcl-2 family proteins is commonly related with tumor maintenance, progression, and chemoresistance. Inhibition of these anti-apoptotic proteins is an attractive approach for cancer therapy. Guided by nuclear magnetic resonance (NMR) binding assays, a series of 5, 5′ substituted compound 6a (Apogossypolone) derivatives was synthesized and identified pan-active antagonists of anti-apoptotic Bcl-2 family proteins, with binding potency in the low micromolar to nanomolar range. Compound 6f inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2 and Mcl-1 with IC50 values of 3.10, 3.12 and 2.05 μM, respectively. In a cellular assay, 6f potently inhibits cell growth in several human cancer cell lines in a dose-dependent manner. Compound 6f further displays in vivo efficacy in transgenic mice and demonstrated superior single-agent antitumor efficacy in a PPC-1 mouse xenograft model. Together with its negligible toxicity, compound 6f represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.
PMCID: PMC3059195  PMID: 21033669
6.  Anthrax Lethal Factor Protease Inhibitors: Synthesis, SAR and Structure-Based 3D QSAR Studies 
Journal of medicinal chemistry  2006;49(1):27-30.
We have recently identified a series of compounds which efficiently inhibit Anthrax lethal factor (LF) metallo-protease. Here we present further structure activity relationship and CoMFA (Comparative Molecular Field Analysis) studies on newly derived inhibitors. The obtained 3D QSAR model was subsequently compared with the X-ray structure of the complex between LF and a representative compound. Our studies form the basis for the rational design of additional compounds with improved activity and selectivity.
PMCID: PMC3164827  PMID: 16392787
7.  BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Anti-apoptotic B-cell lymphoma/leukemia-2 (Bcl-2) Family Proteins 
Journal of medicinal chemistry  2010;53(10):4166-4176.
In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here on synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 0.31, 0.32, 0.20 and 0.62 μM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer and lymphoma cell lines with EC50 values of 0.13, 0.56 and 0.049 μM, respectively and shows little cytotoxicity against bax−/−bak−/− cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.
PMCID: PMC2880850  PMID: 20443627
8.  Multidentate Small-Molecule Inhibitors of Vaccinia H1-related (VHR) Phosphatase Decrease Proliferation of Cervix Cancer Cells 
Journal of medicinal chemistry  2009;52(21):6716-6723.
Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site. This multidentate binding mode was confirmed by Xray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.
PMCID: PMC2790023  PMID: 19888758
9.  Apogossypol Derivatives as Pan-active Inhibitors of Anti-apoptotic B-cell lymphoma/leukemia-2 (Bcl-2) Family Proteins 
Journal of medicinal chemistry  2009;52(14):4511-4523.
Guided by nuclear magnetic resonance (NMR) binding assays and computational docking studies, a series of 5, 5′ substituted Apogossypol derivatives was synthesized that resulted in potent pan-active inhibitors of anti-apoptotic Bcl-2 family proteins. Compound 8r inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 0.76, 0.32, 0.28 and 0.73 μM, respectively. The compound also potently inhibits cell growth of human lung cancer and BP3 human B-cell lymphoma cell lines with EC50 values of 0.33 and 0.66 μM, respectively. Compound 8r shows little cytotoxicity against bax−/−bak−/− cells, indicating that it kills cancers cells via the intented mechanism. The compound also displays in vivo efficacy in transgenic mice in which Bcl-2 is overexpressed in splenic B-cells. Together with its improved chemical, plasma and microsomal stability relative to compound 2 (Apogossypol), compound 8r represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.
PMCID: PMC2747480  PMID: 19555126
10.  Design, Synthesis, and Structure-Activity Relationship of Substrate Competitive, Selective, and in Vivo Active Triazole and Thiadiazole inhibitors of the c-Jun N-Terminal Kinase 
Journal of medicinal chemistry  2009;52(7):1943-1952.
We report comprehensive structure activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that displays promising in vivo activity in mouse models of insulin insensitivity.
PMCID: PMC2667321  PMID: 19271755
11.  Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases 
Journal of medicinal chemistry  2008;51(12):3460-3465.
We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.
PMCID: PMC2825083  PMID: 18494454
12.  Fragment-Based Design of Small Molecule X-Linked Inhibitor of Apoptosis Protein Inhibitors 
Journal of medicinal chemistry  2008;51(22):7111-7118.
We report on a general structure- and NMR- based approach to derive drug-like small molecule inhibitors of protein-protein interactions in a rapid and efficient manner. We demonstrate the utility of the approach by deriving novel and effective SMAC mimetics targeting the anti-apoptotic protein X-Linked Inhibitor of Apoptosis Protein (XIAP). The XIAP baculovirus IAP repeat 3 (Bir3) domain binds directly to the N-terminal of Caspase-9 and thus inhibiting programmed cell death. It has been shown that in the cell this interaction can be displaced by the protein second mitochondrial activator of caspases (SMAC) and that its N-terminal tetrapeptide region (NH2-AVPI, Ala-Val-Pro-Ile) is responsible for this activity. However, due to their limited cell-permeability, synthetic SMAC peptides are inefficient when tested in cultured cells, limiting their use as potential chemical tools or drug candidates against cancer cells. Hence, as an application, we report on the derivation of novel, selective, drug-like, cell permeable SMAC mimics with cellular activity.
PMCID: PMC2692895  PMID: 18956862
13.  Development of molecular probes for second site screening and design of protein tyrosine phosphatase inhibitors 
Journal of medicinal chemistry  2007;50(9):2137-2143.
We report on the design, synthesis and evaluation of series of furanyl-salicyl-nitroxide derivatives, as effective chemical probes for second site screening against phosphotyrosine phosphatases (PTPs) using NMR-based techniques. The compounds have been tested against a panel of PTPs to asses their ability to inhibit a broad spectrum of these phosphatases. The utility of the derived compounds is illustrated with the phosphatase YopH, a bacterial toxin from Yersinia pestis. Novel chemical fragments were identified during a NMR-based screen for compounds that are capable to bind on the surface of YopH in regions adjacent the catalytic site in presence of the spin-labeled compounds. Our data demonstrate the value of the derived chemical probes for NMR-based second-site screening in PTPs.
PMCID: PMC2615387  PMID: 17394300

Results 1-13 (13)