The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond, and those that do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop novel drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs less activity towards metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

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Single-phase epitaxial films of the monoclinic polymorph of BiVO4 were synthesized by reactive molecular-beam epitaxy under adsorption-controlled conditions. The BiVO4 films were grown on (001) yttria-stabilized cubic zirconia (YSZ) substrates. Four-circle x-ray diffraction, scanning transmission electron microscopy (STEM), and Raman spectroscopy confirm the epitaxial growth of monoclinic BiVO4 with an atomically abrupt interface and orientation relationship (001)BiVO4 ∥ (001)YSZ with [100]BiVO4 ∥ [100]YSZ. Spectroscopic ellipsometry, STEM electron energy loss spectroscopy (STEM-EELS), and x-ray absorption spectroscopy indicate that the films have a direct band gap of 2.5 ± 0.1 eV

The self-assembly of uranyl peroxide polyhedra into a rich family of nanoscale cage clusters is thought to be favored by cation templating effects and the pliability of the intrinsically bent U-O2-U dihedral angle. Herein, the importance of ligand and cationic effects on the U-O2-U dihedral angle were explored by studying a family of peroxide-bridged dimers of uranyl polyhedra. Four chemically distinct peroxide-bridged uranyl dimers were isolated that contain combinations of pyridine-2,6-dicarboxylate, picolinate, acetate, and oxalate as coordinating ligands. These dimers were synthesized with a variety of counterions, resulting in the crystallographic characterization of 15 different uranyl dimer compounds containing 17 symmetrically distinct dimers. Eleven of the dimers have U-O2-U dihedral angles in the expected range from 134.0 to 156.3°; however, six have 180° U-O2-U dihedral angles, the first time this has been observed for peroxide-bridged uranyl dimers. The influence of crystal packing, countercation linkages, and π-π stacking impact the dihedral angle. Density functional theory calculations indicate that the ligand does not alter the electronic structure of these systems and that the U-O2-U bridge is highly pliable. Less than 3 kcal·mol(-1) is required to bend the U-O2-U bridge from its minimum energy configuration to a dihedral angle of 180°. These results suggest that the energetic advantage of bending the U-O2-U dihedral angle of a peroxide-bridged uranyl dimer is at most a modest factor in favor of cage cluster formation. The role of counterions in stabilizing the formation of rings of uranyl ions, and ultimately their assembly into clusters, is at least as important as the energetic advantage of a bent U-O2-U interaction.

The neurotensin 1 receptor (NTR1) is an important therapeutic target for a range of disease states including addiction. A high throughput screening campaign, followed by medicinal chemistry optimization, led to the discovery of a non-peptidic β-arrestin biased agonist for NTR1. The lead compound, 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)- piperazin-1-yl)quinazoline, 32 (ML314), exhibits full agonist behavior against NTR1 (EC50 = 2.0 μM) in the primary assay and selectivity against NTR2. The effect of 32 is blocked by the NTR1 antagonist SR142948A in a dose dependent manner. Unlike peptide based NTR1 agonists, compound 32 has no significant response in a Ca2+ mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional Gq coupled pathway. This bias has distinct biochemical and functional consequences that may lead to physiological advantages. Compound 32 displays good brain penetration in rodents, and studies examining its in vivo properties are underway.