9 research outputs found
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library docking’s ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, κ-opioid receptor ligands
were sought with selectivity versus the μ-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library docking’s ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, κ-opioid receptor ligands
were sought with selectivity versus the μ-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library docking’s ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, κ-opioid receptor ligands
were sought with selectivity versus the μ-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library docking’s ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, κ-opioid receptor ligands
were sought with selectivity versus the μ-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Discovery and Rational Design of Pteridin-7(8<i>H</i>)‑one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants
FLT3 has been validated as a therapeutic
target for the treatment of acute myeloid leukemia (AML). In this
paper, we describe for the first time, pteridin-7Â(8<i>H</i>)-one as a scaffold for potent FLT3 inhibitors derived from structural
optimizations on irreversible EGFR inhibitors. The representative
inhibitor (<b>31</b>) demonstrates single-digit nanomolar inhibition
against FLT3 and subnanomolar <i>K</i><sub>D</sub> for drug-resistance
FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows
good selectivity against AML cells harboring FLT3-ITD mutations over
other leukemia and solid tumor cell lines. The mechanism of action
study illustrates that pteridin-7Â(8<i>H</i>)-one derivatives
suppress the phosphorylation of FLT3 and its downstream pathways,
thereby inducing G<sub>0</sub>/G<sub>1</sub> cell cycle arrest and
apoptosis in AML cells. In in vivo studies, <b>31</b> significantly
suppresses the tumor growth in MV4–11 xenograft model. Overall,
we provide a structurally distinct chemical scaffold with which to
develop FLT3 mutants-selective inhibitors for AML treatment
Legislative Documents
Also, variously referred to as: Senate bills; Senate documents; Senate legislative documents; legislative documents; and General Court documents
Design, Synthesis, and Biological Evaluation of Pyrimido[4,5‑<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
First-generation
epidermal growth factor receptor (EGFR) inhibitors,
gefitinib and erlotinib, have achieved initially marked clinical efficacy
for nonsmall cell lung cancer (NSCLC) patients with EGFR activating
mutations. However, their clinical benefit was limited by the emergence
of acquired resistance mutations. In most cases (approximately 60%),
the resistance was caused by the secondary EGFR T790M gatekeeper mutation.
Thus, it is still desirable to develop novel third-generation EGFR
inhibitors to overcome T790M mutation while sparing wild-type (WT)
EGFR. Herein, a series of pyrimidoÂ[4,5-<i>d</i>]Âpyrimidine-2,4Â(1<i>H</i>,3<i>H</i>)-dione derivatives were designed and
synthesized, among which the most potent compound <b>20g</b> not only demonstrated significant inhibitory activity and selectivity
for EGFR<sup>L858R/T790M</sup> and H1975 cells in vitro but also displayed
outstanding antitumor efficiency in H1975 xenograft mouse model. The
encouraging mutant-selective results at both in vitro and in vivo
levels suggested that <b>20g</b> might be used as a promising
lead compound for further structural optimization as potent and selective
EGFR<sup>L858R/T790M</sup> inhibitors
Design, Synthesis, and Biological Evaluation of Pyrimido[4,5‑<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
First-generation
epidermal growth factor receptor (EGFR) inhibitors,
gefitinib and erlotinib, have achieved initially marked clinical efficacy
for nonsmall cell lung cancer (NSCLC) patients with EGFR activating
mutations. However, their clinical benefit was limited by the emergence
of acquired resistance mutations. In most cases (approximately 60%),
the resistance was caused by the secondary EGFR T790M gatekeeper mutation.
Thus, it is still desirable to develop novel third-generation EGFR
inhibitors to overcome T790M mutation while sparing wild-type (WT)
EGFR. Herein, a series of pyrimidoÂ[4,5-<i>d</i>]Âpyrimidine-2,4Â(1<i>H</i>,3<i>H</i>)-dione derivatives were designed and
synthesized, among which the most potent compound <b>20g</b> not only demonstrated significant inhibitory activity and selectivity
for EGFR<sup>L858R/T790M</sup> and H1975 cells in vitro but also displayed
outstanding antitumor efficiency in H1975 xenograft mouse model. The
encouraging mutant-selective results at both in vitro and in vivo
levels suggested that <b>20g</b> might be used as a promising
lead compound for further structural optimization as potent and selective
EGFR<sup>L858R/T790M</sup> inhibitors
Design, Synthesis, and Biological Evaluation of Pyrimido[4,5‑<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
First-generation
epidermal growth factor receptor (EGFR) inhibitors,
gefitinib and erlotinib, have achieved initially marked clinical efficacy
for nonsmall cell lung cancer (NSCLC) patients with EGFR activating
mutations. However, their clinical benefit was limited by the emergence
of acquired resistance mutations. In most cases (approximately 60%),
the resistance was caused by the secondary EGFR T790M gatekeeper mutation.
Thus, it is still desirable to develop novel third-generation EGFR
inhibitors to overcome T790M mutation while sparing wild-type (WT)
EGFR. Herein, a series of pyrimidoÂ[4,5-<i>d</i>]Âpyrimidine-2,4Â(1<i>H</i>,3<i>H</i>)-dione derivatives were designed and
synthesized, among which the most potent compound <b>20g</b> not only demonstrated significant inhibitory activity and selectivity
for EGFR<sup>L858R/T790M</sup> and H1975 cells in vitro but also displayed
outstanding antitumor efficiency in H1975 xenograft mouse model. The
encouraging mutant-selective results at both in vitro and in vivo
levels suggested that <b>20g</b> might be used as a promising
lead compound for further structural optimization as potent and selective
EGFR<sup>L858R/T790M</sup> inhibitors