4 research outputs found
Insights into the Importance of DFD-Motif and Insertion I1 in Stabilizing the DFD-Out Conformation of Mnk2 Kinase
Human
mitogen-activated protein kinases (MAPK)-interacting kinases
1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special
insertions and a DFD-motif that are distinct from other kinases. Crystallographic
studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out
conformation in which residue F227 flips into the ATP binding pocket.
This is rarely observed in other kinases. Although the DFG-out conformation
has attracted great interest for designing selective inhibitors, structural
requirements for binding and the mechanism governing the DFG-out conformation
remain unclear. This work presents for the first time the applicability
of 3D models of Mnk2 protein in studying conformational changes by
utilizing homology modeling and molecular dynamics simulations. The
study reveals that the interactions between residue K234 of insertion
I1 and D226 of the DFD motif play a key role in inducing and stabilizing
the DFD-out conformation. The structural features will aid in the
rational design of Mnk2 inhibitors
Insights into the Importance of DFD-Motif and Insertion I1 in Stabilizing the DFD-Out Conformation of Mnk2 Kinase
Human
mitogen-activated protein kinases (MAPK)-interacting kinases
1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special
insertions and a DFD-motif that are distinct from other kinases. Crystallographic
studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out
conformation in which residue F227 flips into the ATP binding pocket.
This is rarely observed in other kinases. Although the DFG-out conformation
has attracted great interest for designing selective inhibitors, structural
requirements for binding and the mechanism governing the DFG-out conformation
remain unclear. This work presents for the first time the applicability
of 3D models of Mnk2 protein in studying conformational changes by
utilizing homology modeling and molecular dynamics simulations. The
study reveals that the interactions between residue K234 of insertion
I1 and D226 of the DFD motif play a key role in inducing and stabilizing
the DFD-out conformation. The structural features will aid in the
rational design of Mnk2 inhibitors
In Search of Novel CDK8 Inhibitors by Virtual Screening
Aberrant
activity of cyclin-dependent kinase (CDK) 8 is implicated
in various cancers. While CDK8-targeting anticancer drugs are highly
sought-after, no CDK8 inhibitor has yet reached clinical trials. Herein
a large library of drug-like molecules was computationally screened
using two complementary cascades to identify potential CDK8 inhibitors.
Thirty-three hits were identified to inhibit CDK8 and seven of them
were active against colorectal cancer cell lines. Finally, the primary
target was confirmed using three promising hits
Highly Potent, Selective, and Orally Bioavailable 4‑Thiazol‑<i>N</i>‑(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation
Cyclin D dependent kinases (CDK4
and CDK6) regulate entry into
S phase of the cell cycle and are validated targets for anticancer
drug discovery. Herein we detail the discovery of a novel series of
4-thiazol-<i>N</i>-(pyridin-2-yl)Âpyrimidin-2-amine derivatives
as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal
chemistry optimization resulted in <b>83</b>, an orally bioavailable
inhibitor molecule with remarkable selectivity. Repeated oral administration
of <b>83</b> caused marked inhibition of tumor growth in MV4-11
acute myeloid leukemia mouse xenografts without having a negative
effect on body weight and showing any sign of clinical toxicity. The
data merit <b>83</b> as a clinical development candidate