Radu M. Suciu, Armand B. Cognetta, III, Zachary E. Potter, and Benjamin F. Cravatt
ACS Med. Chem. Lett., 2018
DOI: 10.1021/acsmedchemlett.8b00191
Wnt proteins are secreted morphogens that play critical roles in embryonic development and tissue remodeling in adult organisms. Aberrant Wnt signaling contributes to diseases such as cancer. Wnts are modified by an unusual O-fatty acylation event (O-linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. O-Palmitoleoylation of Wnts is introduced by the porcupine (PORCN) acyltransferase and removed by the serine hydrolase NOTUM. PORCN inhibitors are under development for oncology, while NOTUM inhibitors have potential for treating degenerative diseases. Here, we describe the use of activity-based protein profiling (ABPP) to discover and advance a class of N-hydroxyhydantoin (NHH) carbamates that potently and selectively inhibit NOTUM. An optimized NHH carbamate inhibitor, ABC99, preserves Wnt-mediated cell signaling in the presence of NOTUM and was also converted into an ABPP probe for visualizing NOTUM in native biological systems.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs.
Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1
Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...
-
Katharine Gilbert, Aini Vuorinen, Arron Aatkar Peter Pogány, Jonathan Pettinger, Joanna M. Kirkpatrick, Katrin Rittinger∥, David House, Glen...
-
Yejin Jung, Naotaka Noda, Junichiro Takaya, Masahiro Abo, Kohei Toh, Ken Tajiri, Changyi Cui, Lu Zhou, Shin-ichi Sato, and Motonari Uesugi A...
-
Meng Zhang, Angelo Aguilar, Shilin Xu, Liyue Huang, Krishnapriya Chinnaswamy, Taryn Sleger, Bo Wang, Stefan Gross, Brandon N. Nicolay, Sebas...