Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds

Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure–activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms

MOESM1 of Topoisomerase IIβ mediates the resistance of glioblastoma stem cells to replication stress-inducing drugs

Additional file 1: Table S1. Full list of genes on the PCR array

Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent

12noBis-arylidenecycloalkanones structurally related to the nonselective isopeptidase inhibitor G5 were synthesized and tested for cytotoxic activity against glioblastoma cells. Cytotoxicities correlate well with Hammett σ constants for substituted arylidene groups, confirming the proposed inhibition mechanism. A new inhibitor (2c) based on the 4-hydroxycyclohexanone scaffold, which favors apoptosis over necrosis, was selected for further development. 2c inhibited representative deubiquitinases with micromolar IC50, and its proapoptotic activity was studied on several cancer cell lines. Inhibitor 2c was conjugated to PEG via dicarbamate and diester linkers. While the dicarbamate was inactive, the diester (2cPE) behaves like a prodrug and is converted into the active species 2c by secreted esterase activities. Finally, 2cPE was also tested in vivo on A549 lung carcinoma xenografts generated in mice. Intravenous treatment with 2cPE led to a significant reduction in primary tumor growth, without appreciable toxicity to mice.reservedmixedCersosimo, Ulma; Sgorbissa, Andrea; Foti, Carmen; Drioli, Sara; Angelica, Rosario; Tomasella, Andrea; Picco, Raffaella; Semrau, Marta Stefania; Storici, Paola; Benedetti, Fabio; Berti, Federico; Brancolini, ClaudioCersosimo, Ulma; Sgorbissa, Andrea; Foti, Carmen; Drioli, Sara; Angelica, Rosario; Tomasella, Andrea; Picco, Raffaella; Semrau, Marta Stefania; Storici, Paola; Benedetti, Fabio; Berti, Federico; Brancolini, Claudi