Structure-Based Design of Novel Chk1 Inhibitors:  Insights into Hydrogen Bonding and Protein−Ligand Affinity

Abstract

We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.

Aromatische Ringe in chemischer und biologischer Erkennung: Energien und Strukturen

“…[150] Die N-H···p-Wechselwirkungen zwischen Amiden und Seitenketten aromatischer Aminosäuren wurden mithilfe von Peptidmodellsystemen identifiziert und untersucht, [151] z. B. im Falle der Ligandenbindung an Chk1-Kinase, [152] in der der aromatische Ring des Inhibitors (K i = 26 nm) N-H···p-Wechselwirkungen mit der Amid-NH-Gruppe von Ser147/Asp148 eingeht (Abbildung 15). [153] …”

Pharmacophore Modeling and Virtual Screening Studies of Checkpoint Kinase 1 Inhibitors

“…For the pharmacophore modeling algorithm adopted here, the requirements for the training set compounds include: (1) Ͼϭ15 compounds necessary to assure statistical power; (2) activity should span at least 4 orders of magnitude; (3) each order of magnitude represented by Ͼϭ3 compounds; (4) compounds with similar structures should differ in activity by at least one order of magnitude; and (5) compounds with similar activity must be structurally distinct. According to these criteria, we carefully chose twenty-two Chk1 inhibitors, which were collected from different literature resources, [22][23][24][25][26][27][28][29][30][31][32] to form a training set for the generation of quantitative pharmacophore models. Their IC 50 (half maximal inhibitory concentration) values span a range of 6 orders of magnitude (from 0.5 to 31800 nM).…”

Novel Inhibitors of Checkpoint Kinase 1

“…ICOS Corporation, [13] Millennium Pharmaceuticals, [14] and Abbott Laboratories [15] produced early (2003)(2004)(2005) patent applications detailing the inhibitory activity of disubstituted ureas with similar embodiments. Each reported IC 50 value is in the nanomolar range and the preferred embodiment usually contained a functionalized pyrazine as ring I and a disubstituted phenol as ring II (Figure 1). ICOS corporation has disclosed its latest discoveries in a series of patents [16][17][18] based on the general structure 18 ( Figure 2).…”

“…The most preferred configuration has W as a 4-methyl pyrazine, X 1 and X 2 as NH, and Y as O, with varying functionalities appended to the eastern phenyl ring. The compounds represented by this combination exhibit IC 50 values 100 nm in the cell-based Chk1 assay, although some are claimed to be < 25 nm. These prototypical compounds are also at least 20-fold more selective for Chk1 over other protein kinases, including Chk2, CDK1, Akt-1, and p38MapK (some are claimed to have > 75-fold selectivity).…”