2 research outputs found
Discovery and Optimization of a Novel Series of Potent Mutant B‑Raf<sup>V600E</sup> Selective Kinase Inhibitors
B-Raf
represents an attractive target for anticancer therapy and
the development of small molecule B-Raf inhibitors has delivered new
therapies for metastatic melanoma patients. We have discovered a novel
class of small molecules that inhibit mutant B-Raf<sup>V600E</sup> kinase activity both in vitro and in vivo. Investigations into the
structure–activity relationships of the series are presented
along with efforts to improve upon the cellular potency, solubility,
and pharmacokinetic profile. Compounds selectively inhibited B-Raf<sup>V600E</sup> in vitro and showed preferential antiproliferative activity
in mutant B-Raf<sup>V600E</sup> cell lines and exhibited selectivity
in a kinase panel against other kinases. Examples from this series
inhibit growth of a B-Raf<sup>V600E</sup> A375 xenograft in vivo at
a well-tolerated dose. In addition, aminoquinazolines described herein
were shown to display pERK elevation in nonmutant B-Raf cell lines
in vitro
Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors
Janus
kinases (JAKs) have been demonstrated to be critical in cytokine signaling
and have thus been implicated in both cancer and inflammatory diseases.
The JAK family consists of four highly homologous members: JAK1–3
and TYK2. The development of small-molecule inhibitors that are selective
for a specific family member would represent highly desirable tools
for deconvoluting the intricacies of JAK family biology. Herein, we
report the discovery of a potent JAK1 inhibitor, 24, which displays
∼1000-fold selectivity over the other highly homologous JAK
family members (determined by biochemical assays), while also possessing
good selectivity over other kinases (determined by panel screening).
Moreover, this compound was demonstrated to be orally bioavailable
and possesses acceptable pharmacokinetic parameters. In an in vivo
study, the compound was observed to dose dependently modulate the
phosphorylation of STAT3 (a downstream marker of JAK1 inhibition)