Therapeutic potential of targeting the oncogenic SHP2 phosphatase.

摘要: The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there substantial interest in developing SHP2 inhibitors as potential anticancer antileukemia agents. Using a structure-guided fragment-based library approach, we identified novel hydroxyindole carboxylic acid-based inhibitor 11a-1, IC50 value 200 nM greater than 5-fold selectivity against 20 mammalian PTPs. Structural modeling studies reveal that the acid anchors to active site, while interactions oxalamide linker phenylthiophene tail residues β5–β6 loop contribute 11a-1’s binding potency selectivity. Evidence suggests 11a-1 specifically attenuates SHP2-dependent signaling inside cell. Moreover, blocks growth factor mediated Erk1/2 Akt activation exhibits excellent antiproliferative activity ...