Galvanic replacement of semiconducting CuTCNQF4 with Ag+ Ions to enhance electron transfer reaction

Inspired by the electroless galvanic replacement (GR) process where a spontaneous redox reaction occurs between two metal species primarily due to the difference in the standard electrode potential of the metal/metal ion couples, a facile strategy is developed to fabricate hybrid materials of metal organic semiconducting materials. The GR of CuTCNQF4, a metal organic charge transfer complex with Ag+ ion results in the formation of hybrids, wherein at low Ag+ ion concentrations, a hybrid of Ag nanoparticles decorated on the surface of CuTCNQF4 is obtained. In contrast, high Ag+ ion concentrations show the formation of AgTCNQF4/CuTCNQF4 hybrids with Ag nanoparticle decoration on the surface of the CuTCNQF4 structures. While the GR reaction results in different hybrids depending on the concentration of Ag+ ions and the availability of underlying Cu foil, we observe that the resulting hybrids have an influence on the catalytic and electrical properties. The outcomes presented in this work present a strong foundation for fabricating hybrid materials encompassing metal organic charge transfer complexes and exploring their properties for new biological, catalytic and electronic applications

PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy

Sasikumar et al. describe the identification and characterization of CA-170, a small molecule inhibitor of PD-L1 and VISTA. They find that CA-170 activates T cells and exhibits anti-tumor efficacy in mouse models. This study highlights the potential of CA-170, which has advanced to human clinical trials, as an anti-cancer drug

3-Alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor modulators (SARMs) with physicochemical properties suitable for transdermal administration

We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess adequate physicochemical properties for transdermal administration. Compound 26 binds to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activates AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed excellent aqueous solubility of 1.3 g/L at pH 7.4 and an in silico model as well as a customized parallel artificial membrane permeability assay indicate good skin permeation. Indeed, when measuring skin permeation through excised human skin an excellent flux of 2 µg/(cm2*h) was determined without any permeation enhancers. In a two-week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation

Discovery of MAP855, an efficacious and selective MEK1/2 inhibitor with ATP-competitive mode of action

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK inhibitor with efficacy in wildtype (WT) and mutant MEK models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK and a panel of MEK mutant cell lines. Using a structure-based approach, the optimisation addressed the liabilities by systematic analysis of molecular matched pairs (MMP) and ligand conformation. Addition of only 3 heavy atoms to early tool com-pound 6 removed Cyp3A4 liabilities and increased cellular potency by 100-fold, while reducing logP by 5 units. Profiling of MAP855, compound 30 in PK-PD and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK inhibitors. Compound 30 is a novel highly potent and selective MEK1 kinase inhibitor with equipotent inhibition of WT and mutant MEK whose drug like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy

Heightened Measures of Immune Complex and Complement Function and Immune Complex–Mediated Granulocyte Activation in Human Lymphatic Filariasis

The presence of circulating immune complexes (CICs) is a characteristic feature of human lymphatic filariasis. However, the role of CICs in modulating granulocyte function and complement functional activity in filarial infection is unknown. The levels of CICs in association with complement activation in clinically asymptomatic, filarial-infected patients (INF); filarial-infected patients with overt lymphatic pathologic changes (CPDT); and uninfected controls (EN) were examined. Significantly increased levels of CICs and enhanced functional efficiency of the classical and mannose-binding lectin pathways of the complement system was observed in INF compared with CPDT and EN. Polyethylene glycol–precipitated CICs from INF and CPDT induced significantly increased granulocyte activation compared with those from EN, determined by the increased production of neutrophil granular proteins and a variety of pro-inflammatory cytokines. Thus, CIC-mediated enhanced granulocyte activation and modulation of complement function are important features of filarial infection and disease

PROTECTIVE EFFECTS OF VITAMINS C AND E AGAINST ENDOMETRIAL DAMAGE AND OXIDATIVE STRESS IN FLUORIDE INTOXICATION

1. Fluoride (F) is an essential trace element that has protective effects against bone mineral loss. However, it becomes toxic at higher doses and induces some adverse effects on a number of physiological functions, including reproduction. The aims of this study were to examine F-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of vitamins C and E against possible F-induced endometrial impairment in rats. 2. Rats were divided into three groups: control, F and F plus vitamins. The F group was given 100 mg/L orally for 60 days. Combined vitamins were also administered orally. Fluoride administration to control rats significantly increased endometrial malondialdehyde (MDA) but decreased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities. Endometrial glandular and stromal apoptosis were investigated by DNA nick end-labelling (TUNEL) method on each sample and the mean endometrial apoptotic index (AI) was calculated. 3. Vitamin administration with F treatment caused endometrial MDA to decrease, but SOD, GSH-Px and CAT activities to increase, all to significant levels. Vitamins showed a histopathological protection against F-induced endometrial damage. There was a significant difference in the AI between the groups. Lymphocyte and eosinophil infiltration in stroma in F-treated rats were more than those in the control and F + Vit groups. 4. It can be concluded that oxidative endometrial damage plays an important role in F-induced endometrial toxicity, and the modulation of oxidative stress with vitamins reduces F-induced endometrial damage both at the biochemical and histological levels

Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population