3 research outputs found
Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors
Misregulation of protein translation plays a critical
role in human
cancer pathogenesis at many levels. Silvestrol, a cyclopenta[<i>b</i>]benzofuran natural product, blocks translation at the
initiation step by interfering with assembly of the eIF4F translation
complex. Silvestrol has a complex chemical structure whose functional
group requirements have not been systematically investigated. Moreover,
silvestrol has limited development potential due to poor druglike
properties. Herein, we sought to develop a practical synthesis of
key intermediates of silvestrol and explore structure–activity
relationships around the C6 position. The ability of silvestrol and
analogues to selectively inhibit the translation of proteins with
high requirement on the translation–initiation machinery (i.e.,
complex 5′-untranslated region UTR) relative to simple 5′UTR
was determined by a cellular reporter assay. Simplified analogues
of silvestrol such as compounds <b>74</b> and <b>76</b> were shown to have similar cytotoxic potency and better ADME characteristics
relative to those of silvestrol
Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)‑γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate
Optimization of isoquinolinone
PI3K inhibitors led to the discovery
of a potent inhibitor of PI3K-γ (<b>26</b> or IPI-549)
with >100-fold selectivity over other lipid and protein kinases.
IPI-549
demonstrates favorable pharmacokinetic properties and robust inhibition
of PI3K-γ mediated neutrophil migration in vivo and is currently
in Phase 1 clinical evaluation in subjects with advanced solid tumors
Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926
The
formation of the d-homocyclopamine ring system in
IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective
cyclopropanation followed by a stereoselective acid-catalyzed carbocation
rearrangement. In order to perform large-scale cyclopropanation reactions,
we developed new iodomethylzinc bis(aryl)phosphate reagents that were
found to be both effective and safe. These soluble reagents can be
prepared under mild conditions and are stable during the course of
the reaction. Importantly, they have favorable energetics relative
to other cyclopropanating agents such as EtZnCH<sub>2</sub>I. Herein,
we describe the process optimization studies that led to successful
large-scale production of the d-homocyclopamine core necessary
for IPI-926