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Selectivity profiling of compounds is important for kinase drug discovery. To this end, we aimed to develop a broad-range protein kinase assay by synthesizing a novel staurosporine-derived fluorescent probe based on staurosporine and kinase-binding related structural information. Upon structural analysis of staurosporine with kinases, a 4′-methylamine moiety of staurosporine was found to be located on the solvent side of the kinases, to which several linker units can be conjugated by either alkylation or acylation. However, such conjugation was suggested to reduce the binding affinities of the modified compound for several kinases, owing to the elimination of hydrogen bond donor moiety of NH-group from 4′-methylamine and/or steric hindrance by acyl moiety. Based on this structural information, we designed and synthesized a novel staurosporine-based probe without methyl group in order to retain the hydrogen bond donor, similar to unmodified staurosporine. The broad range of the kinase binding assay demonstrated that our novel fluorescent probe is an excellent tool for developing broad-ranging kinase binding assay. [ABSTRACT FROM AUTHOR]

Lysine-specific demethylase 1 (LSD1) is an enzyme that demethylates methylated histone H3 lysine 4 (H3K4). Inhibition of LSD1 enzyme activity could increase H3K4 methylation levels and treat diseases associated with epigenetic dysregulation. However, known LSD1 inhibitors disrupt the interaction between LSD1 and cofactors such as GFI1B, causing the risk of hematological toxicity, including thrombocytopenia. Starting from a known LSD1 inhibitor (±) 1 as a lead compound, a novel series of LSD1 inhibitors that do not induce the expression of GFI1 mRNA, an in vitro surrogate marker of LSD1-GFI1B dissociation, has been designed and synthesized. Initial structure–activity relationship (SAR) studies revealed the structural features key to avoiding GFI1 mRNA induction. Such SAR information enables optimization of LSD1 inhibitors with lowered risk of hematological side effects; TAK-418 ((1 R, 2 R) - 2n), the clinical candidate compound found through this optimization, has a hematological safety profile in rodents and humans. We further confirmed that oral administration of TAK-418 at 0.3 and 1 mg/kg for 2 weeks ameliorated memory deficits in mice with NMDA receptor hypofunction, suggesting potential of efficacy in neurodevelopmental disorders. TAK-418 warrants further investigation as a novel class of LSD1 inhibitors with a superior safety profile for the treatment of CNS disorders. [Display omitted] • Known LSD1 inhibitors have potential hematological toxicity. • A novel series of LSD1 inhibitors, including the clinical candidate TAK-418, have a hematological safety profile. • SAR studies revealed the key structural features of the safety profile. [ABSTRACT FROM AUTHOR]

Abstract: A new synthetic method of α-alkylidene-β-lactam frameworks has been developed. Irradiation of carbamotelluroates 5 having a propargylic group at the nitrogen atom with visible light afforded α-telluromethylene-β-lactams 6 by 4-exo-dig cyclization of carbamoyl radicals, generated by homolytic cleavage of carbamoyl carbon–tellurium bond of 5, with internal C–C triple bond. Density functional theory (DFT) calculations on cyclization step indicate that 4-exo-dig cyclization of carbamoyl radicals is kinetically favored. The existence of a rapid equilibrium between carbamoyl and four-membered vinyl radicals was suggested by control experiments using the corresponding carbamoselenoate. [Copyright &y& Elsevier]