Identification of Cryptotanshinone as an Inhibitor of Oncogenic Protein Tyrosine Phosphatase SHP2 (<i>PTPN11</i>)

Activating mutations of <i>PTPN11</i> (encoding the SHP2 phosphatase) are associated with Noonan syndrome, childhood leukemias, and sporadic solid tumors. Virtual screening combined with experimental assays was performed to identify inhibitors of SHP2 from a database of natural products. This effort led to the identification of cryptotanshinone as an inhibitor of SHP2. Cryptotanshinone inhibited SHP2 with an IC₅₀ of 22.50 μM. Fluorescence titration experiments confirmed that it directly bound to SHP2. Enzymatic kinetic analyses showed that cryptotanshinone was a mixed-type and irreversible inhibitor. This drug was further verified for its ability to block SHP2-mediated cell signaling and cellular functions. Furthermore, mouse myeloid progenitors and patient leukemic cells with the activating mutation E76K in <i>PTPN11</i> were found to be sensitive to this inhibitor. Since cryptotanshinone is used to treat cardiovascular diseases in Asian countries, this drug has a potential to be used directly or to be further developed to treat <i>PTPN11</i>-associated malignancies

Supplementary Material, DS_DISC774248 – High-Throughput Flow Cytometry Identifies Small-Molecule Inhibitors for Drug Repurposing in T-ALL

<p>Supplementary Material, DS_DISC774248 for High-Throughput Flow Cytometry Identifies Small-Molecule Inhibitors for Drug Repurposing in T-ALL by Dominique R. Perez, Christian K. Nick, Anna Waller, Cristina Delgado-Martin, Travis Woods, Nitesh D. Sharma, Michelle L. Hermiston, Mignon L. Loh, Stephen P. Hunger, Stuart S. Winter, Alexandre Chigaev, Bruce Edwards, Larry A. Sklar and Ksenia Matlawska-Wasowska in SLAS Discovery</p