Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties.

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells.

NMR H,C, N resonance assignment of the G12C mutant of human K-Ras bound to GppNHp.

K-Ras exists in two distinct structural conformations specific to binding of GDP and GTP nucleotides. The cycling between an inactive, GDP-bound state and an active, GTP-bound state is regulated by guanine nucleotide exchange factors and GTPase activating proteins, respectively. The activated form of K-Ras regulates cell proliferation, differentiation and survival by controlling several downstream signaling pathways.

[Performance and Mechanism Study of Visible Light-driven CN/BiOBr Composite Photocatalyst].

Efficient visible light-driven CN/BiOBr composite photocatalysts were prepared via a facile hydrothermal method and characterized by X-ray diffraction, Fourier transform infrared, scanning electron microscopy, UV-Vis diffuse reflectance spectra and photoluminescence spectra for the phase composition and optical property. Taking rhodamine B (RhB) as the target pollutant, the photocatalytic activity and stability of photocatalysts were studied under visible light irradiation. Furthermore, the mechanism in the process of photocatalytic degradation was discussed by electron spin resonance spectroscopy analysis and the trapping experiment of generated radicals.

Docking-based virtual screening of potential human P2Y12 receptor antagonists.

Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor, and its antagonists have been widely developed as anti-coagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved satisfactory anti-thrombotic effects, leaving room for further improvement.

A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13.

The proteolysis of VWF by ADAMTS13 is an essential step in the regulation of its hemostatic and thrombogenic potential. The cleavage occurs at strand β4 in the structural core of the A2 domain of VWF, so unfolding of the A2 domain is a prerequisite for cleavage. In the present study, we present the crystal structure of an engineered A2 domain that exhibits a significant difference in the α3-β4 loop compared with the previously reported structure of wild-type A2.

Crystal structures of Saccharomyces cerevisiae tryptophanyl-tRNA synthetase: new insights into the mechanism of tryptophan activation and implications for anti-fungal drug design.

Specific activation of amino acids by aminoacyl-tRNA synthetases is essential for maintaining translational fidelity. Here, we present crystal structures of Saccharomyces cerevisiae tryptophanyl-tRNA synthetase (sTrpRS) in apo form and in complexes with various ligands. In each complex, there is a sulfate ion bound at the active site which mimics the alpha- or beta-phosphate group of ATP during tryptophan activation.

Crystal structure of Pyrococcus horikoshii tryptophanyl-tRNA synthetase and structure-based phylogenetic analysis suggest an archaeal origin of tryptophanyl-tRNA synthetase.

The ancient and ubiquitous aminoacyl-tRNA synthetases constitute a valuable model system for studying early evolutionary events. So far, the evolutionary relationship of tryptophanyl- and tyrosyl-tRNA synthetase (TrpRS and TyrRS) remains controversial. As TrpRS and TyrRS share low sequence homology but high structural similarity, a structure-based method would be advantageous for phylogenetic analysis of the enzymes.