3 research outputs found
Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors
The discovery of somatic Jak2 mutations in patients with
chronic
myeloproliferative neoplasms has led to significant interest in discovering
selective Jak2 inhibitors for use in treating these disorders. A high-throughput
screening effort identified the pyrazolo[1,5-<i>a</i>]pyrimidine
scaffold as a potent inhibitor of Jak2. Optimization of lead compounds <b>7a</b>–<b>b</b> and <b>8</b> in this chemical
series for activity against Jak2, selectivity against other Jak family
kinases, and good in vivo pharmacokinetic properties led to the discovery
of <b>7j</b>. In a SET2 xenograft model that is dependent on
Jak2 for growth, <b>7j</b> demonstrated a time-dependent knock-down
of pSTAT5, a downstream target of Jak2
Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349
Aberrant activation of the PI3K-Akt-mTOR signaling pathway
has
been observed in human tumors and tumor cell lines, indicating that
these protein kinases may be attractive therapeutic targets for treating
cancer. Optimization of advanced lead <b>1</b> culminated in
the discovery of clinical development candidate <b>8h</b>, GDC-0349,
a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349
demonstrates pathway modulation and dose-dependent efficacy in mouse
xenograft cancer models
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 IA(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