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The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico‐chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE‐987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader‐antibody conjugate by attaching GNE‐987 to an anti‐CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen‐specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

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The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) and related chimeric molecules that effect intracellular degradation of target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these chimeric entities are relatively large compounds that often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation of such molecules to monoclonal antibodies using technologies originally developed for cytotoxic payloads so as to provide alternate delivery options for these novel agents. In this report, we describe the first phase of our systematic development of antibody–drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting chimeric degrader entities. We demonstrate the antigen-dependent delivery of the degrader payloads to PC3-S1 prostate cancer cells along with related impacts on MYC transcription and intracellular BRD4 levels. These experiments culminate with the identification of one degrader conjugate, which exhibits antigen-dependent antiproliferation effects in LNCaP prostate cancer cells.

As tea is one of the most popular beverages consumed worldwide, it is important for customers and business investigators to develop an easy and reliable method to discriminate between different types of teas from each other. A total of eighty-seven types of various white, green, oolong, black and Puer teas were collected from the major tea estates in China, and their catechin contents and volatile compounds were compared by high performance liquid chromatograph and gas chromatograph mass spectrometer. It was found green tea contained the highest concentrations of total catechins, ())-epicatechin gallate (ECG) and ())-epigallocatechin gallate (EGCG), while oolong teas contained the highest concentrations of ())-epigallocatechin (EGC) among these five types of teas. The aroma composition and their quantities in different types of teas varied quite widely. The concentration of ECG, EGCG, pentanal, hexanal, methyl jasmonate, indole, (E,E)-2,4-hexadienal and 1,2,3-trimethoxybenzene was shown to be different and could be used to discriminate white, green, oolong, black and Puer teas. The result showed that different types of teas could be partially classified by cluster analysis using index of individual catechins and volatile components.

DNA methylation catalyzed by methyltransferase (MTase) is a significant epigenetic process for modulating gene expression. Traditional methods to study MTase activity require a laborious and costly DNA labeling process. In this article, we report a simple, colorimetric, and label-free methylation-responsive DNAzyme (MR-DNAzyme) strategy for MTase activity analysis. This new strategy relies on horseradish peroxidase (HRP) mimicking DNAzyme and the methylation-responsive sequence (MRS) of DNA which can be methylated and cleaved by the MTase/endonuclease coupling reaction. Methylation-induced scission of MRS would activate the DNAzyme that can catalyze the generation of a color signal for the amplified detection of methylation events. Taking Dam MTase and DpnI endonuclease as examples, we have developed two colorimetric methods based on the MR-DNAzyme strategy. The first method is to utilize an engineered hairpin-DNAzyme hybrid probe for facile turn-on detection of Dam MTase activity, with a wide linear range (6-100 U/mL) and a low detection limit (6 U/mL). Furthermore, this method could be easily expanded to profile the activity and inhibition of restriction endonuclease. The second method involves a methylation-triggered DNAzyme-based DNA machine, which achieves the ultrahigh sensitive detection of Dam MTase activity (detection limit = 0.25 U/mL) by a two-step signal amplification cascade.

Double metal phosphide (NiCoP) with hollow quasi-polyhedron structure was prepared by acidic etching and precipitation of ZIF-67 polyhedra and further phosphorization treatment with NaHPO. The morphology and microstructure of NiCoP quasi-polyhedron and its precursors were investigated by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and a micropore and chemisorption analyzer. Electrocatalytic properties were examined by typical electrochemical methods, such as linear sweep voltammetry, cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy in 1.0 M KOH aqueous solution. Results reveal that, compared with CoP hollow polyhedra, NiCoP hollow quasi-polyhedra exhibit better electrochemical properties for hydrogen evolution with a low onset overpotential of 74 mV and a small Tafel slope of 42 mV dec. When the current density is 10 mA cm, the corresponding overpotential is merely 124 mV, and 93% of its electrocatalytic activity can be maintained for 12 h. This indicates that NiCoP with hollow quasi-polyhedron structure, bimetallic merit, and low cost may be a good candidate as electrocatalyst in the practical application of hydrogen evolution.

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