Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors

From Activity Cliffs to Target‐Specific Scoring Models and Pharmacophore Hypotheses

“…The first group contains the sets that are based on crystal structures. These are structures for the targets PTP-1B (PDB ID: 1NZ7 [21] ) and CHK1 (PDB ID: 2YWP [22] ) taken from the supporting information of a study by Brown and Muchmore. [19] Because all compounds were provided aligned in one single protein structure, which might lead to inaccuracies due to side chain flexibility, we minimized the structures with the program MOE.…”

“…To ensure independence of the external test sets, the DUD2 sets were tested for intersections with the training sets. Because no benchmarked test sets are available for the targets PTP-1B (PDB ID: 1NZ7 [21] ) and CHK1 (PDB ID: 2YWP [22] ), we collected active and decoy sets by following principles similar to those used for the DUD2 data sets. The decoys were collected so that the distributions of a number of descriptors are similar to those of the active compounds.…”

“…The decoys were collected so that the distributions of a number of descriptors are similar to those of the active compounds. In a first step, the actives were collected from the BindingDB [21,22] data base and were tested against the training sets to avoid intersections. Then, the active sets were used to calculate the following descriptors: molecular weight, log P, number of H-bond acceptors, number of H-bond donors, TPSA, number of rotatable bonds, volume, number of atoms, number of bonds, number of aromatic atoms, number of halogen atoms, number of ring systems, number of aromatic ring systems, number of rings, number of aromatic rings, maximum connected rotatable bonds (CRTB), and formal charge.…”

“…[21,22] [b] Collected from the ZINC [30] database with descriptors in the range of mean values AE 2 SD with respect to the active compounds, as described in the Experimental Section.…”

Novel Inhibitors of Checkpoint Kinase 1

“…Compounds 1 and 2 displayed IC 50 values of 8 nm and 7 nm, respectively, and both demonstrated > 200-fold selectivity over several closely related kinases, including Chk2, Akt1, and CDK1. In an attempt to improve the physical properties of the series, such as logP and solubility, the substitution at R 4 position was also investigated, [20] as X-ray analysis shows that attachments here point toward the solvent exposed area. Chk1 inhibition in vitro was evaluated initially, in a radiometric assay conducted in the presence of 5 mm ATP, then in the cell based MTS and FACS assays.…”