2 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 pyrazoloÂ[1,5-<i>a</i>]Âpyrimidine
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 Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors
The discovery and optimization of a series of 6,7-dihydro-5<i>H</i>-cyclopentaÂ[<i>d</i>]Âpyrimidine compounds that
are ATP-competitive, selective inhibitors of protein kinase B/Akt
is reported. The initial design and optimization was guided by the
use of X-ray structures of inhibitors in complex with Akt1 and the
closely related protein kinase A. The resulting compounds demonstrate
potent inhibition of all three Akt isoforms in biochemical assays
and poor inhibition of other members of the cAMP-dependent protein
kinase/protein kinase G/protein kinase C extended family and block
the phosphorylation of multiple downstream targets of Akt in human
cancer cell lines. Biological studies with one such compound, <b>28</b> (GDC-0068), demonstrate good oral exposure resulting in
dose-dependent pharmacodynamic effects on downstream biomarkers and
a robust antitumor response in xenograft models in which the phosphatidylinositol
3-kinase–Akt–mammalian target of rapamycin pathway is
activated. <b>28</b> is currently being evaluated in human clinical
trials for the treatment of cancer