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
Psoromic Acid is a Selective and Covalent Rab-Prenylation Inhibitor Targeting Autoinhibited RabGGTase
Post-translational attachment of geranylgeranyl isoprenoids
to
Rab GTPases, the key organizers of intracellular vesicular transport,
is essential for their function. Rab geranylgeranyl transferase (RabGGTase)
is responsible for prenylation of Rab proteins. Recently, RabGGTase
inhibitors have been proposed to be potential therapeutics for treatment
of cancer and osteoporosis. However, the development of RabGGTase
selective inhibitors is complicated by its structural and functional
similarity to other protein prenyltransferases. Herein we report identification
of the natural product psoromic acid (PA) that potently and selectively
inhibits RabGGTase with an IC<sub>50</sub> of 1.3 μM. Structure–activity
relationship analysis suggested a minimal structure involving the
depsidone core with a 3-hydroxyl and 4-aldehyde motif for binding
to RabGGTase. Analysis of the crystal structure of the RabGGTase:PA
complex revealed that PA forms largely hydrophobic interactions with
the isoprenoid binding site of RabGGTase and that it attaches covalently
to the N-terminus of the α subunit. We found that in contrast
to other protein prenyltransferases, RabGGTase is autoinhibited through
N-terminal <sub>α</sub>His2 coordination with the catalytic
zinc ion. Mutation of <sub>α</sub>His dramatically enhances
the reaction rate, indicating that the activity of RabGGTase is likely
regulated in vivo. The covalent binding of PA to the N-terminus of
the RabGGTase α subunit seems to potentiate its interaction
with the active site and explains the selectivity of PA for RabGGTase.
Therefore, psoromic acid provides a new starting point for the development
of selective RabGGTase inhibitors