posted on 2013-09-26, 00:00authored byWei Liu, Bing Yu, Gang Xu, Wei-Ren Xu, Mignon L. Loh, Li-Da Tang, Cheng-Kui Qu
Activating
mutations of PTPN11 (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 PTPN11 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 PTPN11-associated malignancies.