4 research outputs found
Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling
RIPK2 mediates inflammatory signaling by the bacteria-sensing
receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a
proposed strategy to ameliorate NOD-mediated pathologies. Here,
we reveal that RIPK2 kinase activity is dispensable for NOD2
inflammatory signaling and show that RIPK2 inhibitors function
instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination
of RIPK2. We map the XIAP binding site on RIPK2 to the loop
between b2 and b3 of the N-lobe of the kinase, which is in close
proximity to the ATP-binding pocket. Through characterization of a
new series of ATP pocket-binding RIPK2 inhibitors, we identify the
molecular features that determine their inhibition of both the
RIPK2-XIAP interaction, and of cellular and in vivo NOD2 signaling.
Our study exemplifies how targeting of the ATP-binding pocket in
RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction
for modulation of NOD signaling
A Potential New Treatment Paradigm for Multiple Sclerosis
This project was completed with contributions from Alexei Degterev from the Department of Developmental, Molecular and Chemical Biology, School of Medicine, Tufts University, Boston.Pharmacological and Pharmaceutical Sciences, Department o
Divergent Approach for the Synthesis of Gombamide A and Derivatives
A synthesis of gombamide
A (<b>1</b>) using N-terminal peptide
extension, oxidative disulfide bond formation, and late-stage 4-hydroxystyrylamide
installation has been achieved. This divergent method was also utilized
to synthesize several gombamide A derivatives with modification to
the 4-hydroxystyrylamide via cyclic peptide <b>2</b>. The natural
product and four derivatives were found to be devoid of Na<sup>+</sup>/K<sup>+</sup>-ATPase activity at 10 μM. In addition, the compounds
were not cytotoxic at 10 μM against a panel of cancer cells
Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.
The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties