Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening

Abstract

Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

“…Mitogen-Activated Protein Kinase-Interacting Kinase Inhibitors in the Clinic. A broad array of smallmolecule MNK1/2 inhibitors have been identified to date that encompass diverse chemotypes as represented by Dreas et al (2017), Matsui et al (2018), Jin et al (2019), andMishra et al (2019). Well studied MNK inhibitors include staurosporine, CGP57380, and the natural product, cercosporamide (Fig.…”

MNK Proteins as Therapeutic Targets in Leukemia

“…MNKs have unique structural features that include three short alpha-helices in the catalytic domain, DFD (Asp-Phe-Asp) motifs in the activation loops instead of the usual DFG (Asp-Phe-Gly) motif for other kinases, and an inactive DFD-out conformation with Phe192 in the ATP-binding site which blocks ATP from the catalytic site. 42 Asp228 of the DFD motif stabilizes the DFD-out conformation and is unique to MNKs. 43 These structural features can be exploited in inhibitor design, especially in targeting the inactive MNK forms.…”

Update on the Development of MNK Inhibitors as Therapeutic Agents

“…Mishra et al reported the development and application of a mutation-based induced-fit virtual screening approach leading to the identification of novel MNK inhibitors . Since no crystal structure was available for either DFD-in (active) MNK1 or MNK2 at the time of the study, the authors used the wild-type form of MNK1 to construct models of the active form of the kinase using a mutation-based induced fit docking (IFD) method.…”

“…to the identification of novel MNK inhibitors. 138 Since no crystal structure was available for either DFD-in (active) MNK1 or MNK2 at the time of the study, the authors used the wild-type form of MNK1 to construct models of the active form of the kinase using a mutation-based induced fit docking (IFD) method. IFD of 14 known inhibitors of MNK1 revealed that 3 residues, Phe192, Val63, and Leu55, obstructed the entry of known inhibitors.…”