5 research outputs found
Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate
The
fungal-derived Taiwanese natural product antroquinonol A has attracted
both academic and commercial interest due to its reported exciting
biological properties. This reduced quinone is currently in phase
II trials (USA and Taiwan) for the treatment of non-small-cell lung
carcinoma (NSCLC) and was recently granted orphan drug status by the
FDA for the treatment of pancreatic cancer and acute myeloid leukemia.
Pending successful completion of human clinical trials, antroquinonol
is expected to be commercialized under the trade name Hocena. A synthesis-enabled
biological re-examination of this promising natural product, however,
reveals minimal <i>in vitro</i> and <i>in vivo</i> antitumor activity in preclinical
models
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
The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity
Affinity selection screening of macrocycle
libraries derived from
DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors
that displace bound pro-apoptotic caspases. X-ray cocrystal structures
of key compounds with XIAP BIR2 suggested potency-enhancing structural
modifications. Optimization of dimeric macrocycles with similar affinity
for both domains were potent pro-apoptotic agents in cancer cell lines
and efficacious in shrinking tumors in a mouse xenograft model
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