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This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca2+mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC50of approximately 1.16 μM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity. [ABSTRACT FROM AUTHOR]

An interactive clustering model based on positional weight matrices is described and results obtained using the model to analyze gene regulation patterns in archaea are presented. The 5' flanking sequences of ORFs identified in four archaea, Sulfolobus solfataricus, Pyrobaculum aerophilum, Halobacterium sp. NRC-1, and Pyrococcus abyssi, were clustered using the model. Three regular patterns of clusters were identified for most ORFs. One showed genes with only a ribosome-binding site; another showed genes with a transcriptional regulatory region located at a constant location with respect to the start codon. A third pattern combined the previous two. Both P. aerophilum and Halobacterium sp. NRC-1 exhibited clusters of genes that lacked any regular pattern. Halobacterium sp. NRC-1 also presented regular features not seen in the other organisms. This group of archaea seems to use a combination of eubacterial and eukaryotic regulatory features as well as some unique to individual species. Our results suggest that interactive clustering may be used to examine the divergence of the gene regulatory machinery in archaea and to identify the presence of archaea-specific gene regulation patterns. [ABSTRACT FROM AUTHOR]

Overexpression ofATAD2 (ATPase family, AAA domain containing 2)has been linked to disease severity and progression in a wide rangeof cancers, and is implicated in the regulation of several driversof cancer growth. Little is known of the dependence of these effectsupon the ATAD2 bromodomain, which has been categorized as among theleast tractable of its class. The absence of any potent, selectiveinhibitors limits clear understanding of the therapeutic potentialof the bromodomain. Here, we describe the discovery of a hit froma fragment-based targeted array. Optimization of this produced thefirst known micromolar inhibitors of the ATAD2 bromodomain. [ABSTRACT FROM AUTHOR]