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Summary p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum associated degradation (ERAD) substrates and generation of irresolvable proteotoxic stress leading to activation of the apoptotic arm of the unfolded protein response (UPR). In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway providing a potential strategy for patient selection.

The stoichiometric RuO 2 (110) surface is terminated by bridge-coordinated oxygen atoms (O β ) and by coordinatively unsaturated Ru (Ru cus ) atoms. Exposure to gaseous O 2 leads to the formation of two additional surface species: a molecularly chemisorbed state (O δ ) bridging two neighboring Ru cus atoms and weakly held O atoms (O γ ) in terminal position above the Ru cus atoms. Characterization of the energetics and kinetics as well as structural, vibrational, and electronic properties is achieved by combined application of experimental (low-energy electron diffraction, high-resolution electron loss spectroscopy, thermal desorption spectroscopy) and theoretical (density functional theory) methods. The interplay between the different oxygen species accounts for the high sticking coefficient for dissociative adsorption as well as for the continuous restoration of the surface structure in the course of catalytic oxidation reactions. † Dedicated to Professor J. T. Yates on the occasion of his 65th birthday. Part of the special issue "John T. Yates, Jr. Festschrift".