4 research outputs found
Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
Tankyrase
(TNKS) is a poly-ADP-ribosylating protein (PARP) whose
activity suppresses cellular axin protein levels and elevates β-catenin
concentrations, resulting in increased oncogene expression. The inhibition
of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated
transcription and inhibit tumorigenesis. Compound <b>1</b> is
a previously described moderately potent tankyrase inhibitor that
suffers from poor pharmacokinetic properties. Herein, we describe
the utilization of structure-based design and molecular modeling toward
novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic
properties (<b>39</b>, <b>40</b>)
Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective Na<sub>V</sub>1.7 Inhibitors
The
majority of potent and selective hNa<sub>V</sub>1.7 inhibitors possess
common pharmacophoric features that include a heteroaryl sulfonamide
headgroup and a lipophilic aromatic tail group. Recently, reports
of similar aromatic tail groups in combination with an acyl sulfonamide
headgroup have emerged, with the acyl sulfonamide bestowing levels
of selectivity over hNa<sub>V</sub>1.5 comparable to the heteroaryl
sulfonamide. Beginning with commercially available carboxylic acids
that met selected pharmacophoric requirements in the lipophilic tail,
a parallel synthetic approach was applied to rapidly generate the
derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this
library was elaborated, optimizing for potency and selectivity with
attention to physicochemical properties. The resulting novel leads
are potent, ligand and lipophilic efficient, and selective over hNa<sub>V</sub>1.5. Representative lead <b>36</b> demonstrates selectivity
over other human Na<sub>V</sub> isoforms and good pharmacokinetics
in rodents. The biaryl acyl sulfonamides reported herein may also
offer ADME advantages over known heteroaryl sulfonamide inhibitors
Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
Tankyrases
(TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP)
family. They have been shown to directly bind to axin proteins, which
negatively regulate the Wnt pathway by promoting β-catenin degradation.
Inhibition of tankyrases may offer a novel approach to the treatment
of <i>APC</i>-mutant colorectal cancer. Hit compound <b>8</b> was identified as an inhibitor of tankyrases through a combination
of substructure searching of the Amgen compound collection based on
a minimal binding pharmacophore hypothesis and high-throughput screening.
Herein we report the structure- and property-based optimization of
compound <b>8</b> leading to the identification of more potent
and selective tankyrase inhibitors <b>22</b> and <b>49</b> with improved pharmacokinetic properties in rodents, which are well
suited as tool compounds for further in vivo validation studies