Stable Inhibitor Research Articles

Results from the REPAIR Study Final Analysis: Effects of Macitentan on Right Ventricular (RV) Remodelling in Pulmonary Arterial Hypertension (PAH)

To evaluate the effect of macitentan on RV and hemodynamic properties in PAH patients. REPAIR (NCT02310672) was a 52-week, open-label, single-arm, multicentre study evaluating the effect of macitentan on cardiopulmonary hemodynamics, RV remodelling and function. Primary endpoints were change from baseline (BL) to Week26 in RV stroke volume (RVSV), determined by cardiac MRI; and pulmonary vascular resistance (PVR), determined by right heart catheterization. Secondary endpoints included change from BL to Week 26 in MRI RV cavity volumes and myocardial mass, 6-minute walk distance (6MWD) and WHO functional class (FC). Macitentan 10mg was initiated in treatment-naïve patients, in patients receiving stable background phosphodiesterase type-5 inhibitor [PDE-5i] at BL, or in initial combination with PDE-5i. At a pre-specified interim analysis in 42 patients, both primary endpoints were met. Final supportive analyses included 71 patients with BL and post-BL data for both primary endpoints (modified Full Analysis Set; mFAS). Safety was assessed up to end of study treatment + 30 days in all patients who received ≥1 dose of macitentan (N=87). In the mFAS at BL, mean (SD) age was 45.2 (13.4) years, 57 (80.3%) patients were female, and most patients were FC II (34; 47.9%) and FC III (36; 50.7%); macitentan was initiated as monotherapy in 17(23.9%) patients, on top of stable background PDE-5i therapy in 27 (38.0%) patients and simultaneously with a PDE-5i in 27 (38.0%) patients. RVSV increased by 12 mL and PVR decreased by 38% from BL at Week26 (Table). Meaningful improvements in MRI and 6MWD secondary endpoints were also observed (Table). At Week26, WHO FC (N=71) improved in 40 (56.3%) and was unchanged in 30 (42.3%) patients; none worsened, 1 had missing data. The most common adverse events were peripheral oedema (21.8%), headache (20.7%) and dizziness (13.8%). REPAIR, the first multicentre study in PAH to use RVSV from cardiac MRI as a primary endpoint, showed significant, clinically-relevant improvements in RV function with macitentan as monotherapy or part of combination therapy. Safety was consistent with other macitentan clinical trial data.

Tariquidar-related triazoles as potent, selective and stable inhibitors of ABCG2 (BCRP)

Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in our previous tariquidar analog UR-ME22-1 (9). CuAAC (“click” reaction) gave convenient access to a triazole core as a substitute for the labile amide group and the labile ester moiety was replaced by different acyl groups in a Sugasawa reaction. A stability assay proved the enhancement of the stability in blood plasma. Compounds UR-MB108 (57) and UR-MB136 (59) inhibited ABCG2 in a Hoechst 33342 transport assay with an IC50 value of about 80 nM and belong to the most potent ABCG2 inhibitors described so far. Compound 57 was highly selective, whereas its PEGylated analog 59 showed some potency at ABCB1. Both 57 and 59 produced an ABCG2 ATPase-depressing effect which is in agreement with our precedent cryo-EM study identifying 59 as an ATPase inhibitor that exerts its effect via locking the inward-facing conformation. Thermostabilization of ABCG2 by 57 and 59 can be taken as a hint to comparable binding to ABCG2. As reference substances, compounds 57 and 59 allow additional mechanistic studies on ABCG2 inhibition. Due to their stability in blood plasma, they are also applicable in vivo. The highly specific inhibitor 57 is suited for PET labeling, helping to further elucidate the (patho)physiological role of ABCG2, e.g. at the BBB.

Green synthesis of Citrus reticulata peels extract silver nanoparticles and characterization of structural, biocide and anticorrosion properties

Tangerine peels extract mediated silver nanoparticles (TPE-AgNPs) were synthesized by bio-reduction of silver ions using tangerine (Citrus reticulata) peels extract and characterized using by UV–Vis, XRD, TEM, EDAX, DLS and FTIR. The obtained particles were crystalline, round-shaped, monodisperse and stable. TPE-AgNPs exhibit face centre cubic (fcc) structure in Ag0 (111) phase/orientation with dimension a = b = c = 4.0968 A∘ and α = β = γ = 90° and contain cells with volumes 72.42 × 10−6 pm3 and density (ρ) 10.19 gcm−3. TPE-AgNPs were evaluated as a new material for application as biocide and inhibitor for acid and microbial corrosion of pipeline (X80) steel in oilfield environments. TPE-AgNPs produced a 3-log reduction in microbial population (Desulfovibio sp) at 2.88 mg/L MIC and inhibited biocorrosion by 76.2% and 61.8% at 303 K and 333 K respectively. At these temperatures, 1.0 g/L TPE-AgNPs inhibited X80 steel corrosion in 1 M HCl by efficiency of 93.9% and 90.3%, respectively. Corrosion inhibition occurs by adsorption of the nanoparticles through CO, CC, C–O and O–H sites which increases charge transfer and film resistances at the steel-electrolyte interface. Complementary techniques such as FTIR, SEM/EDAX support electrochemical and weight loss results. TPE-AgNPs were more thermally stable and efficient inhibitors than the crude extract and can be deployed in oilfield for simultaneous inhibition of acid and microbial induced corrosion.

Cysteine-silver-gold Nanocomposite as potential stable green corrosion inhibitor for mild steel under acidic condition

Cysteine based silver-gold nanocomposite (Cys/Ag-Au NCz) was synthesized, this was followed by its characterization using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Ultraviolet-visible spectroscopy (UV-Vis), Scanning electron microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDAX), Thermogravimetric analysis (TGA) and Transmission electron microscopy (TEM). Cys/Ag-Au NCz was studied as novel green corrosion inhibitor for mild steel in 1M HCl solution at varying concentration and temperature using gravimetric, Potentiodynamic polarization (PDP), Electrochemical impedance spectroscopy (EIS), SEM, EDAX and FTIR. Weight loss, PDP and EIS studies confirmed Cys/Ag-Au NCz as efficient corrosion inhibitor at moderately low concentration. The maximum inhibition efficiency of 96 % was observed at 303 K at 300 ppm. Cys/Ag-Au NCz acted by affecting both anodic and cathodic processes and its adsorption on steel surface followed the Langmuir adsorption isotherm. EIS data displayed the existence of protective film at mild steel/solution interface in Cys/Ag-Au NCz inhibited system. SEM micrograph in presence of Cys/Ag-Au NCz inhibited acid solution displayed better morphology as compared to blank solution. The UV-Vis and FTIR data indicates good interaction between the Cys/Ag-Au NCz and steel surface.

The discovery of potent and stable short peptide FGFR1 antagonist for cancer therapy

Fibroblast growth factor receptor 1 (FGFR1) is one of the attractive pharmaceutical targets for cancer therapy. The FGFR1 targeting antagonist peptides, especially of the short peptides harbouring only coding amino acid might highlights promising aspects for their higher affinity, specificity and lower adverse reactions. However, most of peptides inhibitors remain in preclinical research, likely associating with their instability and short half-life. In this study, we found a stable short peptide inhibitor P48 and speculated that its stability might be related to its non-linear spatial structure. In addition, P48 could target the extracellular immunoglobulin domain of FGFR1, and effectively block the particular signaling pathways of FGFR1, which lead to the inhibition of cancer proliferation, invasion in vitro and restraint of tumor growth in vivo. Together, this study provided a promising FGFR1 inhibitor with the potential to be developed as an antitumor drug.

Abstract B117: Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor

Abstract Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease and resistance to ligand binding domain (LBD)-linked therapies inevitably emerges. Mechanisms of resistance to anti-androgens include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (e.g. AR-V7). Inhibition of the N-terminal domain (NTD) of the AR can inhibit transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in anti-androgen refractory mCRPC patients, revealing the need for more potent and metabolically stable NTD inhibitors. EPI-7386 represents a second generation of NTD inhibitors (Anitens) that are more active and more metabolically stable than EPI-506. Methods: Chemical structure activity relationships were explored to increase molecule potency while maintaining target specificity using a wide variety of CRPC models in vivo and in vitro. The stability and selectivity of the molecules were characterized with a panel of selective screening and functional assays. The mechanism of action and pathway engagement markers were followed by qPCR and RNAseq. Results: EPI-7386 was chosen as the IND candidate. The molecule demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity demonstrated in AR-V7-driven cellular models. The antiproliferative effect correlated with the inhibitory effect on AR driven genes, including specifically AR-V7 driven genes such as UBE2C. EPI-7386 controlled tumor growth and induced tumor regressions in several CRPC xenografts, including AR-V7-driven 22Rv1 and enzalutamide resistant LNCaP95 models, as well as the VCaP model. Importantly, the combination of enzalutamide with EPI-7386 demonstrated a more robust and consistent PSA and antitumor response in the VCaP model. EPI-7386 was well tolerated in animal models, and therapeutic levels could be achieved without displaying signs of toxicity in a 14-day rat study. Pharmacodynamic markers will be presented, in addition to their incorporation in the future clinical plan. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506. It shows on-target activity in AR full length and AR-V7 driven models, and demonstrates a high therapeutic index in preclinical models. As a single agent, EPI-7386 may overcome anti-androgen clinical resistance in advanced mCRPC as well as potentially in combination therapy with anti-androgens in earlier stages of the disease. The clinical strategy supporting the development of this Aniten N-terminal domain inhibitor of AR will be discussed. Citation Format: Ronan Le Moigne, C. Adriana Banuelos, Nasrin R Mawji, Teresa Tam, Jun Wang, Kunzhong Jian, Raymond J Andersen, Alessandra Cesano, Marianne D Sadar, Han-Jie Zhou, Peter Virsik. Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B117. doi:10.1158/1535-7163.TARG-19-B117

Acute Respiratory Failure Secondary to ACE Inhibitor–Induced Angioedema after Five Years of Lisinopril Therapy

Angiotensin-converting enzyme (ACE) inhibitors are amongst the commonest prescribed medications in the United States and considered to be the leading causes of drug induced angioedema. High bradykinin levels stimulate vasodilation and increased vascular permeability of the post-capillary venules and allow for plasma extravasation into the submucosal tissue, leading to angioedema. Usually, the angioedema occurs within the first week of exposure to therapy, but cases occurring after years of stable ACE inhibitor usage are not uncommon. Here, we present a 43-year-old Caucasian female who developed acute respiratory failure requiring mechanical ventilation secondary to ACEi–induced angioedema after five years of Lisinopril usage. This case will help to increase physicians’ awareness that this potentially fatal complication can still occur after years of ACE inhibitor usage.

Design, Synthesis, and Biological Evaluation of Novel Indoles Targeting the Influenza PB2 Cap Binding Region.

In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.

503P - EPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer

BackgroundThe androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease. Anti-androgen resistance mechanisms include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (eg. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in mCRPC patients. EPI-7386 is a more potent and stable NTD inhibitor (Anitens) that is advancing to clinical trials. The compounds’ characteristics and the initial clinical study plans including potential biomarkers will be reviewed. MethodsChemical structure activity relationships were developed to increase molecule potency using a wide variety of CRPC models in vivo and in vitro. Similarly, the stability and selectivity of the molecule were characterized with screening and functional assays. Biomarkers were also explored. ResultsEPI-7386 demonstrated a 20 fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostante cancer cell lines, with activity in AR-V7-driven cellular models. EPI-7386 was able to control tumor growth and induce tumor regressions in several CRPC xenografts, including enzalutamide resistant models. In addition, the combination of enzalutamide with EPI-7386 demonstrated a more robust and more homogeneuous antitumor response. Pharmacodynamic markers specific to NTD inhibitors will be presented. ConclusionsThe next generation aniten compound EPI-7386 is more active and more metabolically stable than EPI-002. It demonstrated potential as single agent in overcoming anti-androgen clinical resistance as well as in combination therapy in earlier stages of the disease. The clinical strategy supporting the development of this new generation of Aniten will be discussed. Legal entity responsible for the studyESSA Pharmaceuticals. FundingESSA Pharmaceuticals. DisclosureR. Le Moigne: Full / Part-time employment: ESSA pharma. C.A. Banuelos: Shareholder / Stockholder / Stock options: ESSA pharma. N.R. Mawji: Shareholder / Stockholder / Stock options: ESSA pharma. R.J. Andersen: Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Officer / Board of Directors: ESSA pharma. A. Cesano: Advisory / Consultancy: ESSA pharma; Full / Part-time employment: Nanostring. M.D. Sadar: Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Officer / Board of Directors: ESSA pharma; Speaker Bureau / Expert testimony: Pfizer. H. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: ESSA pharma. P. Virsik: Shareholder / Stockholder / Stock options, Full / Part-time employment: ESSA pharma. All other authors have declared no conflicts of interest.

(10Z)-Debromohymenialdisine from Marine Sponge Stylissa sp. Regulates Intestinal Inflammatory Responses in Co-Culture Model of Epithelial Caco-2 Cells and THP-1 Macrophage Cells.

Crohn’s disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD), are autoimmune diseases characterized by chronic inflammation within the gastrointestinal tract. Debromohymenialdisine is an active pyrrole alkaloid that is well known to serve as a stable and effective inhibitor of Chk2. In the present study, we attempted to investigate the anti-inflammatory properties of (10Z)-debromohymenialdisine (1) isolated from marine sponge Stylissa species using an intestinal in vitro model with a transwell co-culture system. The treatment with 1 attenuated the production and gene expression of lipopolysaccharide (LPS)-induced Interleukin (IL)-6, IL-1β, prostaglandin E2 (PGE2), and tumor necrosis factor-α in co-cultured THP-1 macrophages at a concentration range of 1–5 μM. The protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were down-regulated in response to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation into the nucleus in cells. In addition, we observed that 1 markedly promoted the nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) and subsequent increase of heme oxygenase-1 (HO-1) expression. These findings suggest the potential use of 1 as a pharmaceutical lead in the treatment of inflammation-related diseases including IBD.

Impact of TNF-α inhibitor on lipid profile and atherogenic index of plasma in axial spondyloarthritis: 2-year follow-up data from the Catholic Axial Spondyloarthritis COhort (CASCO).

To evaluate the influence of TNF-α inhibitor on lipid profile and atherogenic index of plasma (AIP) in axial spondyloarthritis (axSpA) patients with long-term use of stable dose TNF-α inhibitor. AxSpA patients were enrolled in the Catholic Axial Spondyloarthritis COhort (CASCO). We collected their data annually and analyzed their lipid profile and AIP. Comparison was conducted between TNF-α inhibitor user group and non-user group. Additionally, lipid profile and AIP of TNF-α inhibitor user group were compared over 2years. A total of 238 axSpA patients were enrolled for the present study, including 132 TNF-α inhibitor users and 106 non-users. Changes of total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL-C), and HDL-C over 2years did not show significant difference between TNF-α inhibitor user group and non-user group. When baseline data and 2-year follow-up data were compared within the TNF-α inhibitor user group, there was no significant increase in TG, LDL-C, HDL-C, or AIP. Only TC level was slightly increased in the 2-year follow-up data for the TNF-α inhibitor user group (177.86 ± 28.73 vs. 183.08 ± 29.82, P = 0.019). Long-term use of stable dose TNF-α inhibitor did not increase atherogenic lipid profile or AIP compared to the control group. Furthermore, atherogenic lipid profile or AIP was not increased significantly in the TNF-α inhibitor user group over the 2-year follow-up. Therefore, using TNF-α inhibitor for a long term might not affect atherosclerosis of axSpA.Key Points• Managing risk factors of cardiovascular disease (CVD) such as dyslipidemia in axSpA is important because axSpA patients have increased risk of CVD.• Using TNF-α inhibitor for 2years with stable dose did not deteriorate atherogenic lipid profile or AIP as predictor of atherosclerosis.• Maintaining stable dose of TNF-α inhibitor for long-term in axSpA may be relatively safe for managing atherogenic lipid.

Characterization, Recombinant Production and Structure-Function Analysis of NvCI, A Picomolar Metallocarboxypeptidase Inhibitor from the Marine Snail Nerita versicolor

A very powerful proteinaceous inhibitor of metallocarboxypeptidases has been isolated from the marine snail Nerita versicolor and characterized in depth. The most abundant of four, very similar isoforms, NvCla, was taken as reference and N-terminally sequenced to obtain a 372-nucleotide band coding for the protein cDNA. The mature protein contains 53 residues and three disulphide bonds. NvCIa and the other isoforms show an exceptionally high inhibitory capacity of around 1.8 pM for human Carboxypeptidase A1 (hCPA1) and for other A-like members of the M14 CPA subfamily, whereas a twofold decrease in inhibitory potency is observed for carboxypeptidase B-like members as hCPB and hTAFIa. A recombinant form, rNvCI, was produced in high yield and HPLC, mass spectrometry and spectroscopic analyses by CD and NMR indicated its homogeneous, compact and thermally resistant nature. Using antibodies raised with rNvCI and histochemical analyses, a preferential distribution of the inhibitor in the surface regions of the animal body was observed, particularly nearby the open entrance of the shell and gut, suggesting its involvement in biological defense mechanisms. The properties of this strong, small and stable inhibitor of metallocarboxypeptidases envisage potentialities for its direct applicability, as well as leading or minimized forms, in biotechnological/biomedical uses.

The significant role of stabilized colloidal ZrO2 nanoparticles for corrosion protection of AA2024

This study reports on the facile synthesis of colloidal ZrO2 nanoparticles with consistent product quality using continuous hydrothermal synthesis. ZrO2 demonstrated particles of 10 nm average particle size using TEM. XRD diffractogram demonstrated high crystalline structure. The fabricated colloidal particles did not flocculate with time. Zeta potential measurement demonstrated stable colloidal particles with Zeta value of +38.5 mV. Colloidal ZrO2 particles as corrosion inhibitor could offer a new approach, where extensive surface area and reactivity can be achieved. The effectiveness of colloidal ZrO2 as a corrosion inhibitor for AA2024 in artificial sea water was evaluated using potentiodynamic polarization and Electrochemical Impedance Spectroscope. ZrO2 nanoparticles improved the corrosion resistance of AA2024 by blocking the intermetallic sites on the metal surface. Consequently colloidal ZrO2 nanoparticles effectively reduced the corrosion rate of AA2024 in the artificial sea water; the corrosion current density of AA2024 was reduced sharply. Inhibition efficiency of 93.6% was achieved. Additionally ZrO2 could act as cathodic inhibitor by suppressing the dealloying of the intermetallic particles. Thanks to hydrothermal processing that offers effective fabrication of novel stable colloidal corrosion inhibitor where extensive surface area and reactivity were accomplished.

Abstract 1292: A new generation of N-terminal domain androgen receptor inhibitors, with improved pharmaceutical properties, in castration-resistant prostate cancer models

Abstract Introduction: The androgen receptor (AR) pathway continues to drive castration-resistant prostate cancer (CRPC) even in late stages of the disease, and ligand binding domain (LBD)-linked resistance inevitably emerges. Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcription even in the presence of anti-androgen resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506 (EPI-002 pro-drug), demonstrated PSA declines in anti-androgen resistant metastatic CRPC patients. However, these declines were minor and of short duration, revealing the need for more potent and metabolically stable NTD inhibitors. A new generation of NTD transcriptional inhibitors (Anitens) has been generated. Examples of this new class, EPI-7170 and EPI-7245, demonstrate improved potency, metabolic stability and pharmaceutical properties, and are potent against anti-androgen resistant prostate cancers in in vitro and in preclinical models. Methods: Chemical structure activity relationships were developed to identify more potent molecules as measured by both cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity were also optimized using a variety of cellular experiments. Results: These next generation Anitens demonstrated a 10-20-fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM compared to 10 uM for EPI-002. Aniten AR inhibition was specific to the NTD, as demonstrated by the absence of LBD binding and the inhibition of the AR-V7-driven transcription inLNCaP95 model. In vitro proliferation assays demonstrated AR-dependent activity, with an IC50 ~ 1 uM in LNCaP and >10 uM in the AR-independent cell model PC-3. The antiproliferative effect aligned with the inhibitory effect on a subset of AR-driven genes. In vivo, next generation Anitens demonstrated PSA serum decreases along with significant tumor growth inhibition in mice bearing LNCaP tumors. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s <500 nM. These new compounds exhibited favorable ADME and PK profiles, with half-life ~ 8 hrs in mice, and predicted low human clearance. Conclusions: Promising next-generation Aniten compounds have been identified which retain the NTD specificity of first-generation agents. These new molecules demonstrate major improvements in potency and metabolic stability in comparison to the first-generation clinical compound EPI-002. These next generation Anitens, by selectively inhibiting AR transcription in both hormone sensitive and castrated resistant prostate cancer, represent an important next step in AR targeted therapeutics. Citation Format: Ronan Le Moigne, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Raymond J. Andersen, Marianne D. Sadar, Han-Jie Zhou, Peter Virsik. A new generation of N-terminal domain androgen receptor inhibitors, with improved pharmaceutical properties, in castration-resistant prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1292.

Modification of <i>Ligustrum vulgare</i> Leaves Extract as Eco-Friendly Corrosion Inhibitors in Oil Fields

Ligustrum vulgare is an evergreen tree. The leaves are opposite, glossy dark green, 6–17 centimetres (2.4–6.7 in) long and 3–8 centimetres (1.2–3.1 in) broad. The ligustrum vulgare leaves contain two main components, one of which is oleanolic acid and the other is p-hydroxyphenylethanol which indicates its extracts suitable to be used as an effective corrosion inhibitor. Extracts of ligustrum vulgare leaves (PE) were modified with hydroxymethylation reaction (PM1) and Mannich reaction (PM2) to produce the relative stable green acidic corrosion inhibitors. The extracts of ligustrum vulgare leaves have been investigated on the corrosion inhibition of A3 steel with weight loss. The results show that these inhibitors have good corrosion inhibition effect on A3 steel. The PM2 are the most effective for corrosion inhibition, and the inhibition efficiency can reach 75.95%. When the temperature is 60°C, the corrosion inhibition rate of PE, PM1, PM2 is only 24.46%, 42.35% and 39.35% respectively which can not effectively prevent the corrosion of the metal. And the extracts inhibit corrosion mainly by adsorption mechanism. This adsorption accords with Langmuir adsorption isotherm.

Biocompatible Macrocyclization between Cysteine and 2-Cyanopyridine Generates Stable Peptide Inhibitors.

Peptides featuring an N-terminal cysteine residue and the unnatural amino acid 3-(2-cyano-4-pyridyl)alanine (Cpa) cyclize spontaneously in aqueous solution at neutral pH. Cpa is readily available and easily introduced into peptides using standard solid-phase peptide synthesis. The reaction is orthogonal to all proteinogenic amino acids, including cysteine residues that are not at the N-terminus. A substrate peptide of the Zika virus NS2B-NS3 protease cyclized in this way produced an inhibitor of high affinity and proteolytic stability.

An Iranian study of group acceptance and commitment therapy versus group cognitive behavioral therapy for adolescents with obsessive-compulsive disorder on an optimal dose of selective serotonin reuptake inhibitors

Conducted in Iran, participants included 69 adolescents with obsessive-compulsive disorder (OCD) who were on a stable selective serotonin reuptake inhibitor (SSRI) dose and were randomly assigned to one of three conditions: group acceptance and commitment therapy (ACT)+SSRI, group cognitive behavioral therapy (CBT)+SSRI, or continued SSRI treatment. Assessment occurred at pre-, post-treatment, and three-month follow-up and included the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Children's Depression Inventory (CDI), Avoidance and Fusion Questionnaire for Youth (AFQ-8), Valued Living Questionnaire (VLQ), and Child and Adolescent Mindfulness Measure (CAMM). ACT + SSRI and CBT + SSRI conditions demonstrated significant reductions in OCD severity that were maintained at follow-up compared to the continued SSRI condition. All conditions demonstrated significant reductions in depression that were maintained at follow-up. The ACT + SSRI condition demonstrated significant improvement in psychological flexibility, mindfulness, and valued living that were maintained at follow-up compared to the CBT + SSRI and continued SSRI conditions. Findings indicate that ACT + SSRI is comparably effective as CBT + SSRI at treating adolescent OCD. However, ACT + SSRI appears to differ from CBT + SSRI on changes in psychological flexibility, mindfulness, and valued living, indicating potential differences in mechanism of change.

Discovery of Baicalin as NDM-1 inhibitor: Virtual screening, biological evaluation and molecular simulation

The emergence and worldwide spreads of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1), has made a great challenge to treat antibiotics-resistant bacterial infections. It can hydrolyse almost all β-lactam antibacterials. Unfortunately, there are no clinically useful inhibitors of NDM-1. In this study, structure-based virtual screening method led to the identification of Baicalin as a novel NDM-1 inhibitor. Inhibitory assays showed that Baicalin possessed a good inhibition of NDM-1 with IC50 values of 3.89 ± 1.1 μM and restored the susceptibility of E.coli BL21(DE3)/pET28a-NDM-1 to clinically used β-lactam antibiotics. Molecular docking and molecular dynamics simulations obtained a complex structure between the relatively stable inhibitor molecule Baicalin and NDM-1 enzyme. The results showed that the carboxyl group in Baicalin directly interacted with the Zn2+ in the active center of the enzyme, and the residues such as Glu152, Gln123, Met67, Trp93 and Phe70 in the enzyme formed hydrogen bonds with Baicalin to further stabilize the complex structure.

Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model

Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system xc-. Among the existing system xc- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system xc- and inducer of ferroptosis potentially suitable for invivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system xc-, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both invitro and invivo. Usinguntargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradablepolyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.

Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin.

Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA synthetase >100-fold more potent than that of the activity registered against the human enzyme. Despite its compelling activity, cladosporin exhibits poor oral bioavailability; a critical requirement for antimalarial drugs. Thus, the quest to develop metabolically stable cladosporin-derived analogues, while retaining similar selectivity and potency to that of the natural compound, has begun. Chemogenomic profiling of a designed library allowed an entirely innovative structure-activity relationship study to be initiated; this shed light on structural evidence of a privileged scaffold with a unique activity against tRNA synthetases.