6 research outputs found
Rational Design of Highly Selective Spleen Tyrosine Kinase Inhibitors
A novel approach to design selective spleen tyrosine
kinase (Syk)
inhibitors is described. Inhibition of spleen tyrosine kinase has
attracted much attention as a mechanism for the treatment of autoimmune
diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib,
a Syk inhibitor that successfully completed phase II clinical trials,
also exhibits some undesirable side effects. More selective Syk inhibitors
could offer safer, alternative treatments. Through a systematic evaluation
of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding
site as a rare combination among sequence aligned kinases and hypothesized
that optimizing the interaction between them and a Syk inhibitor molecule
would impart high selectivity for Syk over other kinases. We report
the structure-guided identification of three series of selective spleen
tyrosine kinase inhibitors that support our hypothesis and offer useful
guidance to other researchers in the field
Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-AcryloylÂpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)Âpyrido[2,3‑<i>d</i>]Âpyrimidin-7(8<i>H</i>)‑one (PRN1371) for the Treatment of Solid Tumors
Aberrant
signaling of the FGF/FGFR pathway occurs frequently in
cancers and is an oncogenic driver in many solid tumors. Clinical
validation of FGFR as a therapeutic target has been demonstrated in
bladder, liver, lung, breast, and gastric cancers. Our goal was to
develop an irreversible covalent inhibitor of FGFR1–4 for use
in oncology indications. An irreversible covalent binding mechanism
imparts many desirable pharmacological benefits including high potency,
selectivity, and prolonged target inhibition. Herein we report the
structure-based design, medicinal chemistry optimization, and unique
ADME assays of our irreversible covalent drug discovery program which
culminated in the discovery of compound <b>34</b> (PRN1371),
a highly selective and potent FGFR1–4 inhibitor
Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-AcryloylÂpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)Âpyrido[2,3‑<i>d</i>]Âpyrimidin-7(8<i>H</i>)‑one (PRN1371) for the Treatment of Solid Tumors
Aberrant
signaling of the FGF/FGFR pathway occurs frequently in
cancers and is an oncogenic driver in many solid tumors. Clinical
validation of FGFR as a therapeutic target has been demonstrated in
bladder, liver, lung, breast, and gastric cancers. Our goal was to
develop an irreversible covalent inhibitor of FGFR1–4 for use
in oncology indications. An irreversible covalent binding mechanism
imparts many desirable pharmacological benefits including high potency,
selectivity, and prolonged target inhibition. Herein we report the
structure-based design, medicinal chemistry optimization, and unique
ADME assays of our irreversible covalent drug discovery program which
culminated in the discovery of compound <b>34</b> (PRN1371),
a highly selective and potent FGFR1–4 inhibitor
Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors
Inhibition
of spleen tyrosine kinase has attracted much attention
as a mechanism for the treatment of cancers and autoimmune diseases
such as asthma, rheumatoid arthritis, and systemic lupus erythematous.
We report the structure-guided optimization of pyridazine amide spleen
tyrosine kinase inhibitors. Early representatives of this scaffold
were highly potent and selective but mutagenic in an Ames assay. An
approach that led to the successful identification of nonmutagenic
examples, as well as further optimization to compounds with reduced
cardiovascular liabilities is described. Select pharmacokinetic and
in vivo efficacy data are presented
Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis
Structure-based
drug design was used to guide the optimization
of a series of selective BTK inhibitors as potential treatments for
Rheumatoid arthritis. Highlights include the introduction of a benzyl
alcohol group and a fluorine substitution, each of which resulted
in over 10-fold increase in activity. Concurrent optimization of drug-like
properties led to compound <b>1</b> (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90),
which was selected for advanced preclinical characterization based
on its favorable properties
Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
PI3Kδ is a lipid kinase and a member of a larger
family of enzymes, PI3K class IAÂ(α, β, δ) and IB
(γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ
is mainly expressed in leukocytes, where it plays a critical, nonredundant
role in B cell receptor mediated signaling and provides an attractive
opportunity to treat diseases where B cell activity is essential,
e.g., rheumatoid arthritis. We report the discovery of novel, potent,
and selective PI3Kδ inhibitors and describe a structural hypothesis
for isoform (α, β, γ) selectivity gained from interactions
in the affinity pocket. The critical component of our initial pharmacophore
for isoform selectivity was strongly associated with CYP3A4 time-dependent
inhibition (TDI). We describe a variety of strategies and methods
for monitoring and attenuating TDI. Ultimately, a structure-based
design approach was employed to identify a suitable structural replacement
for further optimization