Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds.
Screening of the NCI diversity set of compounds has led to the identification of 5 (NSC-117199), which inhibits the protein tyrosine phosphatase (PTP) Shp2 with an IC50 of 47 microM. A focused library incorporating an isatin scaffold was designed and evaluated for inhibition of Shp2 and Shp1 PTP activities. Several compounds were identified that selectively inhibit Shp2 over Shp1 and PTP1B with low to submicromolar activity. A model for the binding of the active compounds is proposed.
Lawrence
Harshani R
HR
Drug Discovery Program, Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, Florida 33612, USA. Harshani.Lawrence@moffitt.org
Pireddu
Roberta
R
Chen
Liwei
L
Luo
Yunting
Y
Sung
Shen-Shu
SS
Szymanski
Ann Marie
AM
Yip
M L Richard
ML
Guida
Wayne C
WC
Sebti
Saïd M
SM
Wu
Jie
J
Lawrence
Nicholas J
NJ
D001665:Binding Sites; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D018909:src Homology Domains / Q000187:drug effects
C531229:3-(2-(2-nitrophenyl)hydrazono)-2-oxoindoline-5-sulfonic acid; D007211:Indoles; D013451:Sulfonic Acids; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6