3 research outputs found
Synthesis of Neplanocin A and Its 3′-Epimer via an Intramolecular Baylis–Hillman Reaction
The key cyclopentenyl intermediate <b>11b</b> was synthesized
in 4 steps from d-ribose in 41% overall yield via an efficient
intramolecular Baylis–Hillman reaction. This novel key intermediate
can be modified easily and transformed to neplanocin A (<b>1a</b>) and its 3′-epimer (<b>1b</b>)
Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
Mitogen-activated
protein kinases-interacting kinase 1 and 2 (Mnk1/2)
activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation.
High level of phosphorylated eIF4E is associated with various types
of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making
them potential therapeutic targets for cancer. Recently, we have designed
and synthesized a series of novel imidazopyridine and imidazopyrazine
derivatives that inhibit Mnk1/2 kinases with a potency in the nanomolar
to micromolar range. In the current work we model the inhibition of
Mnk kinase activity by these inhibitors using various computational
approaches. Combining homology modeling, docking, molecular dynamics
simulations, and free energy calculations, we find that all compounds
bind similarly to the active sites of both kinases with their imidazopyridine
and imidazopyrazine cores anchored to the hinge regions of the kinases
through hydrogen bonds. In addition, hydrogen bond interactions between
the inhibitors and the catalytic Lys78 (Mnk1), Lys113 (Mnk2) and Ser131
(Mnk1), Ser166 (Mnk2) appear to be important for the potency and stability
of the bound conformations of the inhibitors. The computed binding
free energies (Δ<i>G</i><sub>Pred</sub>) of these
inhibitors are in accord with experimental bioactivity data (pIC<sub>50</sub>) with correlation coefficients (<i>r</i><sup>2</sup>) of 0.70 and 0.68 for Mnk1 and Mnk2 respectively. van der Waals
energies and entropic effects appear to dominate the binding free
energy (Δ<i>G</i><sub>Pred</sub>) for each Mnk–inhibitor
complex studied. The models suggest that the activities of these small
molecule inhibitors arise from interactions with multiple residues
in the active sites, particularly with the hydrophobic residues
Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
Clinically used BCR-ABL1
inhibitors for the treatment of chronic
myeloid leukemia do not eliminate leukemic stem cells (LSC). It has
been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E
and eliminate the self-renewal capacity of LSCs. Herein, we describe
the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors,
starting from the known kinase inhibitor <b>2</b>. Initial structure–activity
relationship studies resulted in compound <b>27</b> with loss
of BCR-ABL1 inhibition. Further modification led to orally bioavailable
dual MNK1 and 2 and BCR-ABL1 inhibitors <b>53</b> and <b>54</b>, which are efficacious in a mouse xenograft model and also
reduce the level of phosphorylated eukaryotic translation initiation
factor 4E in the tumor tissues. Kinase selectivity of these compounds
is also presented