Here, the modulation of enzyme activity is presented by protein-imprinted nanoparticles produced using a solid-phase approach. Using trypsin as target, binding of the nanoparticles to the enzyme results in its inhibition or in stabilization, depending on the orientation of the immobilized enzyme used during imprinting.

Herein we discuss five ruthenium(ii) complexes with good cytotoxicity against cancer cells.

Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure−activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.

No abstract

Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug−target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.

No abstract

<div> <p>Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compounds displayed <i>K</i>_D values of 190 nM and 401 nM for VRK1 and VRK2, respectively. Differences in compound binding mode and substituent preferences between the two VRKs were identified by the series structure-activity relationship combined with the crystallographic analysis of key compounds. We expect that our results will serve as a starting point for the design of specific and potent inhibitors against each of the two VRKs based on a pyridine scaffold.</p> </div>

This study aimed to evaluate the effect of organic/conventional coffee in liver tissues in the cancer process, taking into account the level and activities of catalase. The experiments were carried out with 8 groups of rats during 12 weeks. They received two injections of ethylenediaminetetraacetic acid solution 1.5% (v/v) prepared in 0.9% NaCl or 1,2-dimethylhydrazine (DMH) subcutaneous dose of 40 mg·kg−1·bw−1for 2 weeks. The organic/conventional coffee infusions were at 5, 10, and 20% and were incorporated to feed (100 mL of infusion·kg−1of diet). The catalase activity showed a decrease for livers which received DMH and DMH plus organic coffee at 5% and 10%. However, an increase was observed for those receiving organic 20% and conventional 10% coffee, slowing down and favoring the reversibility of the carcinogenic process. By SDS-PAGE, we observed an intensity decrease of 59 kDa bands, as the percentage of coffee was increased. The iron concentration (by ET-AAS) confirmed the electrophoretic results, suggesting that the DMH influenced the catalase expression conditions, reducing the activity by the loss of iron ions. Thus, the coffee may restore the catalase system in the liver, exerting its chemopreventive effects.