10 research outputs found
Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
, 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 is substantial interest in
developing SHP2 inhibitors as potential anticancer and antileukemia
agents. Using a structure-guided and fragment-based library approach,
we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM
and greater than 5-fold selectivity against 20 mammalian PTPs. Structural
and modeling studies reveal that the hydroxyindole carboxylic acid
anchors the inhibitor to the SHP2 active site, while interactions
of the oxalamide linker and the phenylthiophene tail with residues
in the β5–β6 loop contribute
to 11a-1’s binding potency and selectivity.
Evidence suggests that 11a-1 specifically
attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and
Akt activation and exhibits excellent antiproliferative activity in
lung cancer and breast cancer as well as leukemia cell lines