10 research outputs found
Probing the binding mechanism of Mnk inhibitors by docking and molecular dynamics simulations
10.1021/bi501261jBiochemistry54132-4
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
Discovery and Optimization of a Porcupine Inhibitor
Wnt
proteins regulate various cellular functions and serve distinct
roles in normal development throughout life. Wnt signaling is dysregulated
in various diseases including cancers. Porcupine (PORCN) is a membrane-bound <i>O</i>-acyltransferase that palmitoleates the Wnts and hence
is essential for their secretion and function. The inhibition of PORCN
could serve as a therapeutic approach for the treatment of a number
of Wnt-dependent cancers. Herein, we describe the identification of
a Wnt secretion inhibitor from cellular high throughput screening.
Classical SAR based cellular optimization provided us with a PORCN
inhibitor with nanomolar activity and excellent bioavailability that
demonstrated efficacy in a Wnt-driven murine tumor model. Finally,
we also discovered that enantiomeric PORCN inhibitors show very different
activity in our reporter assay, suggesting that such compounds may
be useful for mode of action studies on the PORCN <i>O</i>-acyltransferase
Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors
Porcupine is an <i>O</i>-acyltransferase that regulates Wnt secretion. Inhibiting porcupine
may block the Wnt pathway which is often dysregulated in various cancers.
Consequently porcupine inhibitors are thought to be promising oncology
therapeutics. A high throughput screen against porcupine revealed
several potent hits that were confirmed to be Wnt pathway inhibitors
in secondary assays. We developed a pharmacophore model and used the
putative bioactive conformation of a xanthine inhibitor for scaffold
hopping. The resulting maleimide scaffold was optimized to subnanomolar
potency while retaining good physical druglike properties. A preclinical
development candidate was selected for which extensive in vitro and in vivo profiling is reported
Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.ASTAR (Agency for Sci., Tech. and Research, S’pore
Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
Chronic myeloid leukemia
(CML) is a myeloproliferative disease
caused by <i>bcr-abl1</i>, a constitutively active tyrosine
kinase fusion gene responsible for an abnormal proliferation of leukemic
stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term
relief to CML patients. However, for a proportion of them, BCR-ABL1
inhibition will become ineffective at treating the disease, and CML
will progress to blast crisis (BC) CML with poor prognosis. BC-CML
is often associated with excessive phosphorylated eukaryotic translation
initiation factor 4E (eIF4E), which renders LSCs capable of proliferating
via self-renewal, oblivious to BCR-ABL1 inhibition. <i>In vivo</i>, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently,
a selective inhibitor of MNK1/2 should reduce the level of phosphorylated
eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering
the proliferation of BC LSCs. We report herein the structure–activity
relationships and pharmacokinetic properties of a selective MNK1/2
inhibitor clinical candidate, ETC-206, which in combination with dasatinib
prevents BC-CML LSC self-renewal <i>in vitro</i> and enhances
dasatinib antitumor activity <i>in vivo</i>
Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
Chronic myeloid leukemia
(CML) is a myeloproliferative disease
caused by <i>bcr-abl1</i>, a constitutively active tyrosine
kinase fusion gene responsible for an abnormal proliferation of leukemic
stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term
relief to CML patients. However, for a proportion of them, BCR-ABL1
inhibition will become ineffective at treating the disease, and CML
will progress to blast crisis (BC) CML with poor prognosis. BC-CML
is often associated with excessive phosphorylated eukaryotic translation
initiation factor 4E (eIF4E), which renders LSCs capable of proliferating
via self-renewal, oblivious to BCR-ABL1 inhibition. <i>In vivo</i>, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently,
a selective inhibitor of MNK1/2 should reduce the level of phosphorylated
eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering
the proliferation of BC LSCs. We report herein the structure–activity
relationships and pharmacokinetic properties of a selective MNK1/2
inhibitor clinical candidate, ETC-206, which in combination with dasatinib
prevents BC-CML LSC self-renewal <i>in vitro</i> and enhances
dasatinib antitumor activity <i>in vivo</i>
Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
Chronic myeloid leukemia
(CML) is a myeloproliferative disease
caused by <i>bcr-abl1</i>, a constitutively active tyrosine
kinase fusion gene responsible for an abnormal proliferation of leukemic
stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term
relief to CML patients. However, for a proportion of them, BCR-ABL1
inhibition will become ineffective at treating the disease, and CML
will progress to blast crisis (BC) CML with poor prognosis. BC-CML
is often associated with excessive phosphorylated eukaryotic translation
initiation factor 4E (eIF4E), which renders LSCs capable of proliferating
via self-renewal, oblivious to BCR-ABL1 inhibition. <i>In vivo</i>, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently,
a selective inhibitor of MNK1/2 should reduce the level of phosphorylated
eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering
the proliferation of BC LSCs. We report herein the structure–activity
relationships and pharmacokinetic properties of a selective MNK1/2
inhibitor clinical candidate, ETC-206, which in combination with dasatinib
prevents BC-CML LSC self-renewal <i>in vitro</i> and enhances
dasatinib antitumor activity <i>in vivo</i>
Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
Chronic myeloid leukemia
(CML) is a myeloproliferative disease
caused by <i>bcr-abl1</i>, a constitutively active tyrosine
kinase fusion gene responsible for an abnormal proliferation of leukemic
stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term
relief to CML patients. However, for a proportion of them, BCR-ABL1
inhibition will become ineffective at treating the disease, and CML
will progress to blast crisis (BC) CML with poor prognosis. BC-CML
is often associated with excessive phosphorylated eukaryotic translation
initiation factor 4E (eIF4E), which renders LSCs capable of proliferating
via self-renewal, oblivious to BCR-ABL1 inhibition. <i>In vivo</i>, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently,
a selective inhibitor of MNK1/2 should reduce the level of phosphorylated
eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering
the proliferation of BC LSCs. We report herein the structure–activity
relationships and pharmacokinetic properties of a selective MNK1/2
inhibitor clinical candidate, ETC-206, which in combination with dasatinib
prevents BC-CML LSC self-renewal <i>in vitro</i> and enhances
dasatinib antitumor activity <i>in vivo</i>