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1.  Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors 
ACS Medicinal Chemistry Letters  2012;3(10):793-798.
On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.
PMCID: PMC4025654  PMID: 24900382
metabolic syndrome; enzyme inhibitor; 11β-hydroxysteroid dehydrogenase type 1; sulfonamide; 2-alkylproline; prolinamide
2.  Aminopyrazole–Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies 
ACS Medicinal Chemistry Letters  2013;4(9):829-834.
Herein, we report the lead optimization of amrinone–phenylalanine based GPR142 agonists. Structure–activity relationship studies led to the discovery of aminopyrazole–phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.
PMCID: PMC4027463  PMID: 24900757
GPR142 agonist; type 2 diabetes; aminopyrazole−phenylalanine; insulin secretagogue; prodrug; oral glucose tolerance test; human islet transplant
3.  Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety 
ACS Medicinal Chemistry Letters  2013;4(8):773-778.
We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.
PMCID: PMC4027454  PMID: 24900745
DGAT1; inhibitor; benzimidazole; ACAT1; cyclohexanecarboxylic acid; lipid tolerance test; epimerization; metabolite
4.  Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway 
ACS Medicinal Chemistry Letters  2013;4(4):408-413.
The aberrant function of c-Met kinase signaling pathway is ubiquitously involved in a broad spectrum of human cancers; thus, a strong rationale exists for targeting the kinase pathway in cancer therapy. Via integration of computational and experimental studies, anthraquinone derivatives were identified for the first time as potent c-Met kinase inhibitors in this research. The aberrant activation of the c-Met kinase pathway results from (TPR)-Met, MET gene mutation, or amplification and a hepatocyte growth factor (HGF)/scatter factor-dependent autocrine or paracrine mechanism. However, anthraquinone derivatives exclusively suppressed c-Met phosphorylation stimulated by HGF in A549 cells, indicating that the compounds possess the ability to block the extracellular HGF-dependent pathway. A surface plasmon resonance assay revealed that the most potent compound, 2a, shows a high binding affinity for HGF with an equilibrium dissociation constant of 1.95 μM. The dual roles of compound 2a demonstrate the potency of anthraquinone derivatives and provide a new design solution for the c-Met kinase signaling pathway.
PMCID: PMC4027229  PMID: 24900685
Anthraquinone derivatives; c-Met kinase inhibitors; binding affinity with HGF
5.  Biological Evaluation of New Largazole Analogues: Alteration of Macrocyclic Scaffold with Click Chemistry 
ACS Medicinal Chemistry Letters  2012;4(1):132-136.
We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.
PMCID: PMC4027506  PMID: 24900575
HDAC inhibitor; peptides; macrocycles; largazole; click chemistry
6.  Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design 
PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.
PMCID: PMC4027523  PMID: 24900568
PF-04979064; kinase inhibitor; PI3K/mTOR dual inhibitor; aldehyde oxidase metabolism; cancer; antitumor
7.  Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models 
ACS Medicinal Chemistry Letters  2012;3(2):140-145.
Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.
PMCID: PMC4025649  PMID: 24900443
neurotrophins; NGF; tropomyosin receptor kinase; TRK; oxindole; GNF-5837
8.  Surface-Chemistry Effect on Cellular Response of Luminescent Plasmonic Silver Nanoparticles 
Bioconjugate Chemistry  2014;25(3):453-459.
Cellular response of inorganic nanoparticles (NPs) is strongly dependent on their surface chemistry. By taking advantage of robust single-particle fluorescence and giant Raman enhancements of unique polycrystalline silver NPs (AgNPs), we quantitatively investigated effects of two well-known surface chemistries, passive PEGylation and active c-RGD peptide conjugation, on in vitro behaviors of AgNPs at high temporal and spatial resolution as well as chemical level using fluorescence and Raman microscopy. The results show that specific c-RGD peptide−αvβ3 integrin interactions not only induced endosome formation more rapidly, enhanced constrained diffusion, but also minimized nonspecific chemical interactions between the NPs and intracellular biomolecules than passive PEGylation chemistry; as a result, surface enhanced Raman scattering (SERS) signals of c-RGD peptides were well resolved inside endosomes in the live cells, while Raman signals of PEGylated AgNPs remained unresolvable due to interference of surrounding biomolecules, opening up an opportunity to investigate specific ligand–receptor interactions in real time at the chemical level.
PMCID: PMC3983130  PMID: 24559325
9.  Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development 
ACS Medicinal Chemistry Letters  2013;5(2):124-127.
The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.
PMCID: PMC4027646  PMID: 24900784
MDM2; p53; wild-type; small molecule; apoptosis; cancer
10.  Ethoxysanguinarine Induces Inhibitory Effects and Downregulates CIP2A in Lung Cancer Cells 
ACS Medicinal Chemistry Letters  2013;5(2):113-118.
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is able to stabilize c-Myc oncogenic transcription factor and promote proliferation and transformation of cells. CIP2A is overexpressed in many primary tumors, and pharmacological inactivation of CIP2A is an emerging concept for the development of novel anticancer agents. In this study, we demonstrate that overexpression of CIP2A predicts poor prognosis in lung cancer, and a natural compound, ethoxysanguinarine (ESG), effectively downregulates CIP2A protein and its downstream signaling molecules, c-Myc and pAkt, and induces protein phosphatase 2A (PP2A) activity. ESG inhibits proliferation and induces apoptosis of lung cancer cells, and enhances the effects of cisplatin on malignant cells. Taken together, our findings demonstrate that CIP2A is inversely associated with the clinical outcome of lung cancer, and ESG can serve as a lead compound for the development of CIP2A inhibitor for cancer therapies.
PMCID: PMC4027744  PMID: 24900782
Ethoxysanguinarine; CIP2A; lung cancer; cell proliferation; apoptosis
11.  Holographic Photopolymer Linear Variable Filter with Enhanced Blue Reflection 
ACS Applied Materials & Interfaces  2014;6(5):3081-3087.
A single beam one-step holographic interferometry method was developed to fabricate porous polymer structures with controllable pore size and location to produce compact graded photonic bandgap structures for linear variable optical filters. This technology is based on holographic polymer dispersed liquid crystal materials. By introducing a forced internal reflection, the optical reflection throughout the visible spectral region, from blue to red, is high and uniform. In addition, the control of the bandwidth of the reflection resonance, related to the light intensity and spatial porosity distributions, was investigated to optimize the optical performance. The development of portable and inexpensive personal health-care and environmental multispectral sensing/imaging devices will be possible using these filters.
PMCID: PMC3985781  PMID: 24517443
holographic polymer dispersed liquid crystals; holographic photopatterning; graded rainbow-colored reflection grating
12.  Dynamic Determination of Active-Site Reactivity in Semiquinone Photolyase by the Cofactor Photoreduction 
Photolyase contains a flavin cofactor in a fully reduced form as its functional state to repair ultraviolet-damaged DNA upon blue light absorption. However, after purification, the cofactor exists in its oxidized or neutral semiquinone state. Such oxidization eliminates the repair function, but it can be reverted by photoreduction, a photoinduced process with a series of electron-transfer (ET) reactions. With femtosecond absorption spectroscopy and site-directed mutagenesis, we completely recharacterized such photoreduction dynamics in the semiquinone state. Comparing with all previous studies, we identified a new intramolecular ET pathway, determined stretched ET behaviors, refined all ET time scales, and finally evaluated the driving forces and reorganization energies for eight elementary ET reactions. Combined with the oxidized-state photoreduction dynamics, we elucidated the different active-site properties of the reduction ability and structural flexibility in the oxidized and semiquinone states, leading to the dramatically different ET dynamics and photoreduction efficiency in the two states.
PMCID: PMC3985926  PMID: 24803991
13.  Mechanistic Consequences of Chiral Radical Clock Probes: Analysis of the Mononuclear Non-Heme Iron Enzyme HppE with 2-Hydroxy-3-methylenecyclopropyl Radical Clock Substrates 
(S)-2-Hydroxypropylphosphonic acid [(S)-HPP] epoxidase (HppE) is a mononuclear iron enzyme that catalyzes the last step in the biosynthesis of the antibiotic fosfomycin. HppE also processes the (R)-enantiomer of HPP but converts it to 2-oxo-propylphosphonic acid. In this study, all four stereoisomers of 3-methylenecyclopropyl-containing substrate analogues, (2R, 3R)-8, (2R, 3S)-8, (2S, 3R)-8, and (2S, 3S)-8, were synthesized and used as radical probes to investigate the mechanism of the HppE-catalyzed reaction. Upon treatment with HppE, (2S, 3R)-8 and (2S, 3S)-8 were converted via a C1 radical intermediate to the corresponding epoxide products, as anticipated. In contrast, incubation of HppE with (2R, 3R)-8 led to enzyme inactivation, and incubation of HppE with (2R, 3S)-8 yielded the 2-keto product. The former finding is consistent with the formation of a C2 radical intermediate, where the inactivation is likely triggered by radical-induced ring cleavage of the methylenecyclopropyl group. Reaction with (2R, 3S)-8 is predicted to also proceed via a C2 radical intermediate, but no enzyme inactivation and no ring-opened product were detected. These results strongly suggest that an internal electron transfer to the iron center subsequent to C–H homolysis competes with ring-opening in the processing of the C2 radical intermediate. The different outcomes of the reactions with (2R, 3R)-8 and (2R, 3S)-8 demonstrate the need to carefully consider the chirality of substituted cyclopropyl groups as radical reporting groups in studies of enzymatic mechanisms.
PMCID: PMC4004275  PMID: 24512048
14.  The Active Site Sulfenic Acid Ligand in Nitrile Hydratases Can Function as a Nucleophile 
Nitrile hydratase (NHase) catalyzes the hydration of nitriles to their corresponding commercially valuable amides at ambient temperatures and physiological pH. Several reaction mechanisms have been proposed for NHase enzymes however, the source of the nucleophile remains a mystery. Boronic acids have been shown to be potent inhibitors of numerous hydrolytic enzymes due to the open shell of boron, which allows it to expand from a trigonal planar (sp2) form to a tetrahedral form (sp3). Therefore, we examined the inhibition of the Co-type NHase from Pseudonocardia thermophila JCM 3095 (PtNHase) by boronic acids via kinetics and X-ray crystallography. Both 1-butaneboronic acid (BuBA) and phenylboronic acid (PBA) function as potent competitive inhibitors of PtNHase. X-ray crystal structures for BuBA and PBA complexed to PtNHase were solved and refined at 1.5, 1.6 and 1.2 Å resolution. The resulting PtNHase-boronic acid complexes represent a “snapshot” of reaction intermediates and implicate the cysteine-sulfenic acid ligand as the catalytic nucleophile, a heretofore unknown role for the αCys113-OH sulfenic acid ligand. Based on these data, a new mechanism of action for the hydration of nitriles by NHase is presented.
PMCID: PMC3968781  PMID: 24383915
15.  Identification of ML251, a Potent Inhibitor of T. brucei and T. cruzi Phosphofructokinase 
Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure–activity relationships within the series.
PMCID: PMC4027769  PMID: 24900769
Trypanosoma brucei; Trypanosoma cruzi; phosphofructokinase; inhibitors; glycolysis; high-throughput screening
16.  Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists 
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
PMCID: PMC4027777  PMID: 24900774
RORγt; agonists; inverse agonists; Th17 cell differentiation; cocrystal structure; structure-based design
17.  Evaluation of Aminohydantoins as a Novel Class of Antimalarial Agents 
Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure–activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.
PMCID: PMC4027786  PMID: 24900778
Malaria; antimalarial; aminohydantoin; medicinal chemistry; aspartic protease inhibitors
18.  The Active Site Sulfenic Acid Ligand in Nitrile Hydratases Can Function as a Nucleophile 
Nitrile hydratase (NHase) catalyzes the hydration of nitriles to their corresponding commercially valuable amides at ambient temperatures and physiological pH. Several reaction mechanisms have been proposed for NHase enzymes; however, the source of the nucleophile remains a mystery. Boronic acids have been shown to be potent inhibitors of numerous hydrolytic enzymes due to the open shell of boron, which allows it to expand from a trigonal planar (sp2) form to a tetrahedral form (sp3). Therefore, we examined the inhibition of the Co-type NHase from Pseudonocardia thermophila JCM 3095 (PtNHase) by boronic acids via kinetics and X-ray crystallography. Both 1-butaneboronic acid (BuBA) and phenylboronic acid (PBA) function as potent competitive inhibitors of PtNHase. X-ray crystal structures for BuBA and PBA complexed to PtNHase were solved and refined at 1.5, 1.6, and 1.2 Å resolution. The resulting PtNHase–boronic acid complexes represent a “snapshot” of reaction intermediates and implicate the cysteine-sulfenic acid ligand as the catalytic nucleophile, a heretofore unknown role for the αCys113–OH sulfenic acid ligand. Based on these data, a new mechanism of action for the hydration of nitriles by NHase is presented.
PMCID: PMC3968781  PMID: 24383915
19.  Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors 
ACS Medicinal Chemistry Letters  2013;4(12):1203-1207.
Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure–activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing’s syndrome.
PMCID: PMC4027133  PMID: 24900631
Inhibitor; CYP11B2; aldosterone synthase; aldosterone; hypertension; enzyme; CYP11B1; Cushing’s syndrome; cortisol
20.  Adamantyl Derivative As a Potent Inhibitor of Plasmodium FK506 Binding Protein 35 
ACS Medicinal Chemistry Letters  2013;4(11):1097-1101.
FKBP35, FK506 binding protein family member, in Plasmodium species displays a canonical peptidyl-prolyl isomerase (PPIase) activity and is intricately involved in the protein folding process. Inhibition of PfFKBP35 by FK506 or its analogues were shown to interfere with the in vitro growth of Plasmodium falciparum. In this study, we have synthesized adamantyl derivatives, Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c, which demonstrate submicromolar inhibition of Plasmodium falciparum FK506 binding domain 35 (FKBD35) PPIase activity. SRA and its analogues not only inhibit the in vitro growth of Plasmodium falciparum 3D7 strain but also show stage specific activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the Plasmodium vivax FKBD35 PPIase activity and our crystal structure of PvFKBD35 in complex with the SRA provides structural insights in achieving selective inhibition against Plasmodium FKBPs.
PMCID: PMC4027365  PMID: 24900611
FK506 binding protein; FKBP35; peptidyl-prolyl-isomerase; immunophilin; chaperone
21.  Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR 
ACS Medicinal Chemistry Letters  2013;4(10):974-978.
This letter describes the construction of conformationally constrained quinazoline analogues. Structure–activity relationship studies led to the identification of the lead compound 9n. Compound 9n exhibits effective in vitro activity against A431WT,overexpression and H1975[L858R/T790M] cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.
PMCID: PMC4027470  PMID: 24900594
Anticancer; kinase inhibitor; EGFR; conformationally constrained
22.  Largazole Arrests Cell Cycle at G1 Phase and Triggers Proteasomal Degradation of E2F1 in Lung Cancer Cells 
ACS Medicinal Chemistry Letters  2013;4(10):921-926.
Aberration in cell cycle has been shown to be a common occurrence in lung cancer, and cell cycle inhibitor represents an effective therapeutic strategy. In this study, we test the effects of a natural macrocyclic depsipeptide largazole on lung cancer cells and report that this compound potently inhibits the proliferation and clonogenic activity of lung cancer cells but not normal bronchial epithelial cells. Largazole arrests cell cycle at G1 phase with up-regulation of the expression of cyclin-dependent kinase inhibitor p21. Interestingly, largazole enhances the E2F1-HDAC1 binding affinity and induces a proteasomal degradation of E2F1, leading to suppression of E2F1 function in lung cancer but not normal bronchial epithelial cells. Because E2F1 is overexpressed in lung cancer tumor samples, these data indicate that largazole is an E2F1-targeting cell cycle inhibitor, which bears therapeutic potentials for this malignant neoplasm.
PMCID: PMC4027503  PMID: 24900585
Lung cancer; cell cycle; largazole; E2F1; degradation
23.  Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes 
ACS Medicinal Chemistry Letters  2013;4(8):790-794.
GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.
PMCID: PMC4027368  PMID: 24900747
GPR142; agonist; insulin secretagogue; diabetes; glucose lowering
24.  Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site 
ACS Medicinal Chemistry Letters  2014;5(7):736-741.
Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding pocket (LBP). Here, we report the identification and characterization of a new RXRα transcriptional antagonist by using structure-based virtual screening. The new antagonist binds with submicromolar affinity to RXRα (Kd = 4.88 × 10–7 M) and selectively inhibits RXRα transactivation. The compound does not bind to the LBP but to a hydrophobic groove on the surface of RXRα. The new compound also effectively suppresses AKT activation and promotes apoptosis of cancer cells in a RXRα-dependent manner by inhibiting tRXRα interaction with the p85α subunit of PI3K. Thus, the compound represents a new RXRα modulator that regulates the nongenomic actions of RXRα by surface binding.
PMCID: PMC4094270  PMID: 25057340
RXRα; coregulator-binding site; RXRα antagonist; nongenomic actions; virtual screening
25.  Selective Catecholamine Recognition with NeuroSensor 521: A Fluorescent Sensor for the Visualization of Norepinephrine in Fixed and Live Cells 
ACS Chemical Neuroscience  2013;4(6):918-923.
A method for the selective labeling and imaging of catecholamines in live and fixed secretory cells is reported. The method integrates a tailored approach using a novel fluorescence-based turn-on molecular sensor (NeuroSensor 521) that can exploit the high concentration of neurotransmitters and acidic environment within secretory vesicles for the selective recognition of norepinephrine and dopamine. The utility of the method was demonstrated by selectively labeling and imaging norepinephrine in secretory vesicles such that discrimination between norepinephrine- and epinephrine-enriched populations of chromaffin cells was observed. This method was validated in fixed cells by co-staining with an anti-PNMT antibody.
PMCID: PMC3708293  PMID: 23527575
Fluorescent sensor; catecholamine; norepinephrine; cell imaging; chromaffin

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