Related Experiment Video
Updated: Apr 28, 2026

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase
Vasiliy N Korotchenko1, Manush Saydmohammed, Laura L Vollmer
1Department of Pharmaceutical Sciences, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15213 (USA); Present address: Walter Reed Army Institute of Research, 503 Forney Drive, Silver Spring, MD 20910 (USA).
Abstract:
Dual specificity phosphatase 6 (DUSP6) functions as a feedback attenuator of fibroblast growth factor signaling during development. In vitro high throughput chemical screening attempts to discover DUSP6 inhibitors have yielded limited success. However, in vivo whole-organism screens of zebrafish identified compound 1 (BCI) as an allosteric inhibitor of DUSP6. Here we designed and synthesized a panel of analogues to define the structure-activity relationship (SAR) of DUSP6 inhibition. In vivo high-content analysis in transgenic zebrafish, coupled with cell-based chemical complementation assays, identified structural features of the pharmacophore of 1 that were essential for biological activity. In vitro assays of DUSP hyperactivation corroborated the results from in vivo and cellular SAR. The results reinforce the notion that DUSPs are druggable through allosteric mechanisms and illustrate the utility of zebrafish as a model organism for in vivo SAR analyses.
Related Concept Videos
Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein Kinases and Phosphatases
Allosteric Regulation
Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Ligand Binding and Linkage
Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:

