2 research outputs found
Discovery of Potent KIFC1 Inhibitors Using a Method of Integrated High-Throughput Synthesis and Screening
KIFC1
(HSET), a member of the kinesin-14 family of motor proteins,
plays an essential role in centrosomal bundling in cancer cells, but
its function is not required for normal diploid cell division. To
explore the potential of KIFC1 as a therapeutic target for human cancers,
a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold
was developed from hits identified through high-throughput screening
(HTS). Optimization of the initial hits combined both design–synthesis–test
cycles and an integrated high-throughput synthesis and biochemical
screening method. An important aspect of this integrated method was
the utilization of DMSO stock solutions of compounds registered in
the corporate compound collection as synthetic reactants. Using this
method, over 1500 compounds selected for structural diversity were
quickly assembled in assay-ready 384-well plates and were directly
tested after the necessary dilutions. Our efforts led to the discovery
of a potent KIFC1 inhibitor, <b>AZ82</b>, which demonstrated
the desired centrosome declustering mode of action in cell studies
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)