Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma.

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment

Multi-Feature Manifold Discriminant Analysis for Hyperspectral Image Classification

Hyperspectral image (HSI) provides both spatial structure and spectral information for classification, but many traditional methods simply concatenate spatial features and spectral features together that usually lead to the curse-of-dimensionality and unbalanced representation of different features. To address this issue, a new dimensionality reduction (DR) method, termed multi-feature manifold discriminant analysis (MFMDA), was proposed in this paper. At first, MFMDA explores local binary patterns (LBP) operator to extract textural features for encoding the spatial information in HSI. Then, under graph embedding framework, the intrinsic and penalty graphs of LBP and spectral features are constructed to explore the discriminant manifold structure in both spatial and spectral domains, respectively. After that, a new spatial-spectral DR model for multi-feature fusion is built to extract discriminant spatial-spectral combined features, and it not only preserves the similarity relationship between spectral features and LBP features but also possesses strong discriminating ability in the low-dimensional embedding space. Experiments on Indian Pines, Heihe and Pavia University (PaviaU) hyperspectral data sets demonstrate that the proposed MFMDA method performs significantly better than some state-of-the-art methods using only single feature or simply stacking spectral features and spatial features together, and the classification accuracies of it can reach 95.43%, 97.19% and 96.60%, respectively

Introduction to the themed collection on Covalent Drug Discovery

Guest editors Keriann Backus, Zhengying Pan and Lyn Jones introduce the themed collection on Covalent Drug Discovery

Synthesis of Highly Substituted Imidazolidine-2,4-dione (Hydantoin) through Tf₂O‑Mediated Dual Activation of Boc-Protected Dipeptidyl Compounds

Highly substituted chiral hydantoins were readily synthesized from simple dipeptides in a single step under mild conditions. This reaction proceeded through the dual activation of an amide and a <i>tert</i>-butyloxycarbonyl (Boc) protecting group by Tf₂O-pyridine. This method was successfully applied in the preparation of a variety of biologically active compounds, including drug analogs and natural products

Melting behaviour of gold nanowires in carbon nanotubes

The melting temperature and behaviour of gold nanowire in a single-walled carbon nanotube (SWNT) were investigated in detail using molecular dynamics simulations. The results showed that the melting temperature of the enclosed Au nanowire is lower than its bulk counterpart and higher than that observed for free-standing ones. Different from the melting behaviour of freestanding Au nanowires, the melting of Au nanowires enclosed in SWNTs with tube diameters (D) in the range 1.08 nm >D>2.09 nm investigated here was found to initiate from the centre layers. The predicted melting temperature and behaviour of gold nanowires in SWNTs were clearly shown to be dependent on the interaction between C and Au atoms. The interaction is helpful to further stabilize the structure of enclosed Au nanowires, in particular, the outermost layer. © 2011 Taylor & Francis.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Development of a Selective Labeling Probe for Bruton’s Tyrosine Kinase Quantification in Live Cells

As a key regulator of the B-cell receptor signaling pathway, Bruton’s tyrosine kinase (Btk) has emerged as an important therapeutic target for various malignancies and autoimmune disorders. However, data on the expression profiles of Btk are lacking. Here, we report the discovery of a new, selective Btk probe and of a sandwich-type ELISA quantification method to detect endogenous Btk in live cells. We achieved selective labeling of Btk in vivo and quantified Btk levels in seven types of human lymphoma cell lines. This quantification method provides a powerful tool to study Btk in live cells that may also be useful in clinical settings

Site-Selective Protein Immobilization by Covalent Modification of GST Fusion Proteins

The immobilization of functional proteins onto solid supports using affinity tags is an attractive approach in recent development of protein microarray technologies. Among the commonly used fusion protein tags, glutathione <i>S</i>-transferase (GST) proteins have been indispensable tools for protein–protein interaction studies and have extensive applications in recombinant protein purification and reversible protein immobilization. Here, by utilizing pyrimidine-based small-molecule probes with a sulfonyl fluoride reactive group, we report a novel and general approach for site-selective immobilization of Schistosoma japonicum GST (<i>sj</i>GST) fusion proteins through irreversible and specific covalent modification of the tyrosine-111 residue of the <i>sj</i>GST tag. As demonstrated by <i>sj</i>GST-tagged eGFP and <i>sj</i>GST-tagged kinase activity assays, this immobilization approach offers the advantages of high immobilization efficiency and excellent retention of protein structure and activity

Discovery of a Series of 2,5-Diaminopyrimidine Covalent Irreversible Inhibitors of Bruton’s Tyrosine Kinase with in Vivo Antitumor Activity

Bruton’s tyrosine kinase (Btk) is an attractive drug target for treating several B-cell lineage cancers. Ibrutinib is a first-in-class covalent irreversible Btk inhibitor and has demonstrated impressive effects in multiple clinical trials. Herein, we present a series of novel 2,5-diaminopyrimidine covalent irreversible inhibitors of Btk. Compared with ibrutinib, these inhibitors exhibited a different selectivity profile for the analyzed kinases as well as a dual-action mode of inhibition of both Btk activation and catalytic activity, which counteracts a negative regulation loop for Btk. Two compounds from this series, <b>31</b> and <b>38</b>, showed potent antiproliferative activities toward multiple B-cell lymphoma cell lines, including germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) cells. In addition, compound <b>31</b> significantly prevented tumor growth in a mouse xenograft model