4 research outputs found
Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity
The
prominent role of IAPs in controlling cell death and their
overexpression in a variety of cancers has prompted the development
of IAP antagonists as potential antitumor therapies. We describe the
identification of a series of heterodimeric antagonists with highly
potent antiproliferative activities in cIAP- and XIAP-dependent cell
lines. Compounds <b>15</b> and <b>17</b> further demonstrate
curative efficacy in human melanoma and lung cancer xenograft models
and are promising candidates for advanced studies
Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity
The
prominent role of IAPs in controlling cell death and their
overexpression in a variety of cancers has prompted the development
of IAP antagonists as potential antitumor therapies. We describe the
identification of a series of heterodimeric antagonists with highly
potent antiproliferative activities in cIAP- and XIAP-dependent cell
lines. Compounds <b>15</b> and <b>17</b> further demonstrate
curative efficacy in human melanoma and lung cancer xenograft models
and are promising candidates for advanced studies
Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer
A series of dimeric macrocyclic compounds
were prepared and evaluated
as antagonists for inhibitor of apoptosis proteins. The most potent
analogue <b>11</b>, which binds to XIAP and c-IAP proteins with
high affinity and induces caspase-3 activation and ultimately cell
apoptosis, inhibits growth of human melanoma and colorectal cell lines
at low nanomolar concentrations. Furthermore, compound <b>11</b> demonstrated significant antitumor activity in the A875 human melanoma
xenograft model at doses as low as 2 mg/kg on a q3d schedule
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
JAK2 kinase inhibitors are a promising
new class of agents for
the treatment of myeloproliferative neoplasms and have potential for
the treatment of other diseases possessing a deregulated JAK2-STAT
pathway. X-ray structure and ADME guided refinement of C-4 heterocycles
to address metabolic liability present in dialkylthiazole <b>1</b> led to the discovery of a clinical candidate, BMS-911543 (<b>11</b>), with excellent kinome selectivity, <i>in vivo</i> PD activity, and safety profile