5 research outputs found
Evaluation of Novel Synthetic Methods for the Preparation of the Sodium Channel Inhibitor, GW273225X
The evaluation of efficient synthetic
methods for the preparation
of (<i>R</i>)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine,
GW273225X (<b>1</b>), is described. The initial synthesis using
ethylfluoroacetate was evaluated against three alternative routes
using either nucleophilic fluorination, electrophilic fluorination,
or sodium fluoroacetate
Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis
Potent
and selective inhibitors of Dyrk1B kinase were developed
to explore the hypothesis, based on siRNA studies, that Dyrk1B may
be a resistance mechanism in cells undergoing a stress response
Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2
The RAS/RAF/MEK/ERK signaling pathway
has been targeted with a
number of small molecule inhibitors in oncology clinical development
across multiple disease indications. Importantly, cell lines with
acquired resistance to B-RAF and MEK inhibitors have been shown to
maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors.
There are a number of selective, noncovalent ERK1/2 inhibitors reported
along with the promiscuous hypothemycin (and related analogues) that
act via a covalent mechanism of action. This article reports the identification
of multiple series of highly selective covalent ERK1/2 inhibitors
informed by structure-based drug design (SBDD). As a starting point
for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical
series identified via high-throughput screening were exploited. These
approaches resulted in the identification of selective covalent tool
compounds for potential <i>in vitro</i> and <i>in vivo</i> studies to assess the risks and or benefits of targeting this pathway
through such a mechanism of action
Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point
There are a number of small-molecule
inhibitors targeting the RAS/RAF/MEK/ERK
signaling pathway that have either been approved or are in clinical
development for oncology across a range of disease indications. The
inhibition of ERK1/2 is of significant current interest, as cell lines
with acquired resistance to BRAF and MEK inhibitors have been shown
to maintain sensitivity to ERK1/2 inhibition in preclinical models.
This article reports on our recent work to identify novel, potent,
and selective reversible ERK1/2 inhibitors from a low-molecular-weight,
modestly active, and highly promiscuous chemical start point, compound <b>4</b>. To guide and inform the evolution of this series, inhibitor
binding mode information from X-ray crystal structures was critical
in the rapid exploration of this template to compound <b>35</b>, which was active when tested in in vivo antitumor efficacy experiments
Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
A novel series of small-molecule
inhibitors has been developed
to target the double mutant form of the epidermal growth factor receptor
(EGFR) tyrosine kinase, which is resistant to treatment with gefitinib
and erlotinib. Our reported compounds also show selectivity over wild-type
EGFR. Guided by molecular modeling, this series was evolved to target
a cysteine residue in the ATP binding site via covalent bond formation
and demonstrates high levels of activity in cellular models of the
double mutant form of EGFR. In addition, these compounds show significant
activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to
their observed clinical efficacy. A glutathione (GSH)-based assay
was used to measure thiol reactivity toward the electrophilic functionality
of the inhibitor series, enabling both the identification of a suitable
reactivity window for their potency and the development of a reactivity
quantitative structure-property relationship (QSPR) to support design