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. 2010 Mar 25;53(6):2482-93.
doi: 10.1021/jm901645u.

Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

Xian Zhang  1 , Yantao He, Sijiu Liu, Zhihong Yu, Zhong-Xing Jiang, Zhenyun Yang, Yuanshu Dong, Sarah C Nabinger, Li Wu, Andrea M Gunawan, Lina Wang, Rebecca J Chan, Zhong-Yin Zhang
Affiliations

Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

Xian Zhang et al. J Med Chem. .

Abstract

The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.

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Figures

Figure 1
Figure 1
Strategy for the construction of an indole salicylic acid based library using click chemistry.
Figure 2
Figure 2
Chemical structures of 53 amines and hydrazines.
Figure 3
Figure 3
Compound 9 is a noncompetitive inhibitor of SHP2. Lineweaver-Burk plot for compound 9-mediated SHP2 inhibition. Compound 9 concentrations were 0 (•), 1.0 (μ), and 5.0 μM (τ), respectively.
Figure 4
Figure 4
Compound 9 inhibits SHP2-dependent ERK1/2 activation. (A) Immunoblot showing phospho-ERK1/2 levels from 0 to 60 minute time points of EGF stimulation of HEK293 cells in the presence or absence of 10 μM compound 9; (B) Concentration dependence of inhibition of the EGF-induced sustained ERK1/2 activation by 9 in HEK293 cells.
Figure 5
Figure 5
Compound 9 inhibits GM-CSF-stimulated bone marrow low density mononuclear cell proliferation. (A) and (B) Bone marrow low density mononuclear cells retrovirally transduced with wild-type SHP2, SHP2/D61Y, or SHP2/E76K were serum- and growth factor-deprived, stimulated with increasing concentrations of GM-CSF (0 – 1 ng/mL) in the presence or absence of 10 μM compound 9, and subjected to 3H-thymidine incorporation to measure cellular proliferation; n=3, *p<0.005 for DMSO vs. 9 for both SHP2/D61Y- and SHP2/E76K-expressing cells at all concentrations of GM-CSF.
Figure 6
Figure 6
Crystal structure of SHP2 in complex with 9. (A) Ribbon diagram of SHP2 catalytic domain in complex with inhibitor 9. The molecule is oriented with the C-terminal end of the β8 strand toward the viewer. α-helices and β-strands are colored in red and yellow, respectively. The P-loop is shown in green and the WPD loop in blue. Compound 9 is shown in stick-and-bond mode. (B) Fo-Fc difference map of SHP2 contoured at 3.0 σ level.
Figure 7
Figure 7
Detailed interactions between SHP2 and 9. The P-loop and WPD loop are shown in green and blue, respectively. Atomic colors are as follows: oxygen - red, carbon – grey, sulfur - orange, and nitrogen - blue. Ligand's carbon atoms are colored yellow. Polar interactions are highlighted with red dash lines.
Figure 8
Figure 8
Superposition of SHP2•9 and PTP1B•pY (PDB entry code 1EEN). The superposition was calculated with active site residues without the ligands. Active site of PTP1B is in the WPD loop closed conformation, pY is shown in yellow, the WPD loop is in blue, and the P-loop and other residues in green. For SHP2•9 structure, the WPD loop is in the open conformation, with 9 shown in red, WPD loop in orange, the P-loop in green, Y279 and R465 in pink, and W423, P424, D425, H426, and G427 in grey.
Figure 9
Figure 9
Amino acid sequence alignment of the β5-β6 loop among the PTPs.
Scheme I
Scheme I
Synthesis of the alkyne-containing salicylic acid core 1. Conditions: a) Me2SO4, Na2CO3, acetone, r.t., 86%; b) (CH2O)n, NaCNBH3, AcOH, r.t., 78%; c) I2, K2CO3, water, r.t., 42%; d) Phenylacetylene, Pd(PPh3)2Cl2, CuI, Et3N, DMF, 89%; e) I2, CH2Cl2, r.t., 87%; f) Trimethylsilylacetylene, Pd(PPh3)2Cl2, CuI, Et3N, DMF, r.t., 73%; g) TBAF, THF, r.t., 69%; h) KOH, THF/H2O, reflux, 38%.
Scheme II
Scheme II
Synthesis of azide-tagged diversity elements.
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