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In the past decade, CHK2 has emerged as an important multifunctional player in the DNA-damage response signalling pathway. Parallel studies of the human CHEK2 gene have also highlighted its role as a candidate multiorgan tumour susceptibility gene rather than a highly penetrant predisposition gene for Li-Fraumeni syndrome. As discussed here, our current(More)
FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal(More)
Hand held long exposures often result in blurred photographs due to camera shake. Long exposures are desirable both for artistic effect and in low-light situations. We propose a novel method for digitally reducing imaging artifacts, which does not require additional hardware such as tripods or optical image stabilization lenses. A series of photographs is(More)
Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the(More)
Research into inhibitors of the protein kinases controlling the cellular response to DNA damage has reached an exciting stage, particularly for the checkpoint kinases CHK1 and CHK2. Selective inhibitors are now being tested in clinical trials in cancer patients. In this review, we highlight recent data from cellular and in vivo preclinical models that(More)
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have(More)
Ire1 (Ern1) is an unusual transmembrane protein kinase essential for the endoplasmic reticulum (ER) unfolded protein response (UPR). Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA(More)
A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5(More)
Although the crystal structure of the anti-cancer target protein kinase B (PKBbeta/Akt-2) has been useful in guiding inhibitor design, the closely related kinase PKA has generally been used as a structural mimic due to its facile crystallization with a range of ligands. The use of PKB-inhibitor crystallography would bring important benefits, including a(More)
Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that is activated in response to hypoxia and growth factors. HIF-1 plays a central role in tumor progression, invasion, and metastasis. Overexpression of the HIF-1alpha subunit has been observed in many human cancers and is associated with a poor prognostic outcome with conventional treatments.(More)