3 research outputs found
Discovery of <i>N</i>‑[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors
The overexpression
of AXL kinase has been described in many types
of cancer. Due to its role in proliferation, survival, migration,
and resistance, AXL represents a promising target in the treatment
of the disease. In this study we present a novel compound family that
successfully targets the AXL kinase. Through optimization and detailed
SAR studies we developed low nanomolar inhibitors, and after further
biological characterization we identified a potent AXL kinase inhibitor
with favorable pharmacokinetic profile. The antitumor activity was
determined in xenograft models, and the lead compounds reduced the
tumor size by 40% with no observed toxicity as well as lung metastasis
formation by 66% when compared to vehicle control
Discovery of <i>N</i>‑[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors
The overexpression
of AXL kinase has been described in many types
of cancer. Due to its role in proliferation, survival, migration,
and resistance, AXL represents a promising target in the treatment
of the disease. In this study we present a novel compound family that
successfully targets the AXL kinase. Through optimization and detailed
SAR studies we developed low nanomolar inhibitors, and after further
biological characterization we identified a potent AXL kinase inhibitor
with favorable pharmacokinetic profile. The antitumor activity was
determined in xenograft models, and the lead compounds reduced the
tumor size by 40% with no observed toxicity as well as lung metastasis
formation by 66% when compared to vehicle control
Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors
Activating mutations in the epidermal
growth factor receptor (EGFR)
have been identified in a subset of non-small cell lung cancer (NSCLC),
which is one of the leading cancer types worldwide. Application of
EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary
EGFR mutations or by amplification of the hepatocyte growth factor
receptor (<i>c-Met</i>) gene. Although several EGFR and
c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors,
which can overcome this latter resistance mechanism, have hitherto
not been published and have not reached clinical trials. In the present
study we have identified dual EGFR/c-Met inhibitors and designed novel <i>N</i>-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives,
which inhibit the c-Met receptor and both the wild-type and the activating
mutant EGFR kinases in nanomolar range. We have demonstrated by Western
blot analysis that compound <b>10</b> inhibits EGFR and c-Met
phosphorylation at cellular level and effectively inhibits viability
of the NSCLC cell lines