Ian Collins

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..Potent PKB inhibitors from this series inhibited GSK3beta phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells...

..We show how chemical biology approaches offer techniques for interconnecting elements of the traditional linear progression from gene to drug, thereby providing a basis for increasing speed and success in cancer drug discovery...

..Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses...

..We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials...

..Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors...

..These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold...

..A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice...

..In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533)...

..Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2...

..Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera...

..The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2...

..SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility...

..g. poly(ADP-ribose) polymerase inhibitors]. We also consider the single-agent activity of checkpoint kinase inhibitors for tumours with defined genetic backgrounds...

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..01% Triton X100. The authors now include an interference assay during hit confirmation procedures and check compound activity in the presence of Triton X100 in an attempt to eliminate nonspecific aggregators at an early stage...

..Compounds with selectivity for PKB over PKA and other kinases were identified by this approach, resulting in potent inhibitors with in vivo activity through both oral and systemic administration, and suitable for further development...

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..The level of newly published patent applications covering CHK1 and CHK2 inhibitors remains high and a diverse range of scaffolds has been claimed...

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..These studies identify human Ire1? as a target for development of ATP-competitive inhibitors that will modulate the UPR in human cells, which has particular relevance for myeloma and other secretory malignancies...

..Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors...

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..Our cell-based assay approach has successfully identified novel compounds that differentially target hypoxia and/or growth factor-mediated induction of HIF-1alpha...

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..In the acetylation arm, two compounds increased cellular acetylation, one of which inhibited histone deacetylase activity. A third compound decreased cellular histone acetylation, potentially through a novel mechanism of action...

..An elaborated lead compound showed cell growth inhibition and effects on cellular signaling pathways characteristic of PKB inhibition...

..Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%...

..The synthesis of five fused-bicyclic medium-ring lactones carrying identical ring-fusion to that in the polyether toxins is described using an enolate hydroxylation, intramolecular hydrosilation, Claisen rearrangement sequence...

..We provide a structural explanation for this difference, and highlight the ability of PKA-PKB to mimic the true PKB binding mode in this case...

..Because the compound affected the tumor cells at a lower concentration than primary keratinocytes, it may have potential as an antitumor therapy...

..aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy...

..Conditions have been developed for the two-step conversion of the ketone 12 under thermodynamic control into the racemic tricyclic 6,6,5-adduct 16 which is the core precursor of all the known histrionicotoxin alkaloids...