9 research outputs found
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
Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors
Protein kinase C iota (PKC-ι)
is an atypical kinase implicated
in the promotion of different cancer types. A biochemical screen of
a fragment library has identified several hits from which an azaindole-based
scaffold was chosen for optimization. Driven by a structure–activity
relationship and supported by molecular modeling, a weakly bound fragment
was systematically grown into a potent and selective inhibitor against
PKC-ι
Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors
Protein kinase C iota (PKC-ι)
is an atypical kinase implicated
in the promotion of different cancer types. A biochemical screen of
a fragment library has identified several hits from which an azaindole-based
scaffold was chosen for optimization. Driven by a structure–activity
relationship and supported by molecular modeling, a weakly bound fragment
was systematically grown into a potent and selective inhibitor against
PKC-ι
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
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>