15965-57-8Relevant articles and documents
Nonpolar isosteres of damaged DNA bases: Effective mimicry of mutagenic properties of 8-oxopurines
Taniguchi, Yosuke,Kool, Eric T.
, p. 8836 - 8844 (2007)
A substantial fraction of mutations that arise in the cell comes from oxidative damage to DNA bases. Oxidation of purine bases at the 8-position, yielding 8-oxo-G and 8-oxo-A, results in conformational changes (from anti to syn) that cause miscoding durin
Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening
Kilchmann, Falco,Marcaida, Maria J.,Kotak, Sachin,Schick, Thomas,Boss, Silvan D.,Awale, Mahendra,G?nczy, Pierre,Reymond, Jean-Louis
, p. 7188 - 7211 (2016/09/09)
Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
Nakao, Syuhei,Mabuchi, Miyuki,Shimizu, Tadashi,Itoh, Yoshihiro,Takeuchi, Yuko,Ueda, Masahiro,Mizuno, Hiroaki,Shigi, Naoko,Ohshio, Ikumi,Jinguji, Kentaro,Ueda, Yuko,Yamamoto, Masatatsu,Furukawa, Tatsuhiko,Aoki, Shunji,Tsujikawa, Kazutake,Tanaka, Akito
supporting information, p. 1071 - 1074 (2014/03/21)
A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5- methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.