The
RSK2 kinase is a downstream effector of the Ras/Raf/MEK/ERK pathway that is aberrantly active in a range of
cancer types and has been recognized an anticancer target. The inhibition of
RSK2 kinase activity would disrupt multiple pro-
cancer processes; however, there are few RSK2 inhibitors. The data have been obtained for a series of
pteridinone-,
pyrimidine-,
purine-, and
pyrrolopyrimidine-based compounds, developed to establish a structure-activity relationship for RSK inhibition. The compounds were docked into the
ATP-binding site of the N-terminal domain of the
RSK2 kinase using Glide. The binding conformations of these molecules was then used to generate a set of pharmacophore models to determine the structural requirements for RSK2 inhibition. Through the combination of these models, common features (pharmacophores) can be identified that can inform the development of further small molecule RSK inhibitors. The synthesis and evaluation of the
pteridinone- and
pyrimidine-based compounds was reported in the related articles: Substituted
pteridinones as p90 ribosomal S6
protein kinase (RSK) inhibitors: A structure-activity study (Casalvieri et al., 2020) and Molecular docking of substituted
pteridinones and
pyrimidines to the
ATP-binding site of the N-terminal domain of RSK2 and associated MM/GBSA and molecular field datasets (Casalvieri et al., 2020). [1], [2]. The synthesis and evaluation of the
purine- and
pyrrolopyrimidine-based compounds was reported in the related research article: N-substituted pyrrolopyrimidines and
purines as p90 ribosomal S6
protein kinase-2 (RSK2) inhibitors (Casalvieri et al., 2021) [3].