5 research outputs found
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 <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>