3 research outputs found
Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles
A novel selective benzoxazepin inhibitor
of PI3Kδ has been discovered. Beginning from compound <b>3</b>, an αPI3K inhibitor, we utilized structure-based drug
design and computational analysis of dihedral torsion angles to optimize
for PI3Kδ isoform potency and isoform selectivity. Further medicinal
chemistry optimization of the series led to the identification of <b>24</b>, a highly potent and selective inhibitor of PI3Kδ
Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor
Inhibitors
targeting the activating mutants of the epidermal growth
factor receptor (EGFR) have found success in the treatment of EGFR
mutant positive non-small-cell lung cancer. A secondary point mutation
(T790M) in the inhibitor binding site has been linked to the acquired
resistance against those first generation therapeutics. Herein, we
describe the lead optimization of a series of reversible, pan-mutant
(L858R, del<sub>746–750,</sub> T790M/L858R, and T790M/del<sub>746–750</sub>) EGFR inhibitors. By use of a noncovalent double
mutant (T790M/L858R and T790M/del<sub>746–750</sub>) selective
EGFR inhibitor (<b>2</b>) as a starting point, activities against
the single mutants (L858R and del<sub>746–750</sub>) were introduced
through a series of structure-guided modifications. The in vitro ADME-PK
properties of the lead molecules were further optimized through a
number of rational structural changes. The resulting inhibitor (<b>21</b>) exhibited excellent cellular activity against both the
single and double mutants of EGFR, demonstrating target engagement
in vivo and ADME-PK properties that are suitable for further evaluation.
The reversible, noncovalent inhibitors described complement the covalent
pan-mutant EGFR inhibitors that have shown encouraging results in
recent clinical trials
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