Fatty acids as natural specific inhibitors of the proto-oncogenic protein Shp2 Dongping Liu a,  , Guiping Kong a,  , Quan Cheng Chen a , Guanghui Wang a , Jie Li a , Yang Xu a , Ting lin a , Yingpu Tian a , Xiaokun Zhang a,b , Xinsheng Yao a,c , Gensheng Feng a,d , Zhongxian Lu a,⇑ , Haifeng Chen a,⇑ a School of Pharmaceutical Sciences, Xiamen City Key Laboratory of Metabolism Disease, Xiamen University, Xiamen 361005, PR China b Cancer Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA c Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China d Molecular Pathology Graduate Program, University of California San Diego, La Jolla, CA 92093, USA article info Article history: Received 11 May 2011 Revised 25 August 2011 Accepted 7 September 2011 Available online 13 September 2011 Keywords: Shp2 inhibitors Angelica dahurica Fatty acid Cell apoptosis abstract Src homology-2 domain-containing protein tyrosine phosphatase (Shp2), a novel proto-oncogenic protein, is an important target in cancer therapy research. Approximately 2000 plant extracts were screened to find its natural specific inhibitors, with the ethyl acetate (EtOAc) active extract of the root of Angelica dahurica showing considerable inhibitory effects (IC 50 = 21.6 mg/L). Bioguided isolation of EtOAc extract led to 13 compounds, including 10 fatty acids and derivatives. All these compounds were isolated from the plant for the first time. The inhibitory effects of these compounds on the enzyme activities of Shp2, VH1-related human protein (VHR), and hematopoietic protein tyrosine phosphatase (HePTP) were investigated. 8Z,11Z- Feptadecadienoic acid (4), 14Z,17Z-tricosadienoic acid (5), caffeic acid (9), and 2-hydroxy-3-[(1-oxodode- cyl) oxy]propyl-b-D-glucopyranoside (11) showed considerable selective inhibition of Shp2 activity. After treatment of HepG2 cells with the compounds, only compound 5, a polyunsaturated fatty acid, strongly induced poly (ADP-ribose) polymerase (PARP) cleavage in a dose- and time-dependent manner and increased the activities of caspase-3, caspase-8, and caspase-9 at 100 lM. Compound 5 also inhibited colony formation of HepG2 cells in a dose-dependent manner. Thus, this study reported fatty acids as specific Shp2 inhibitors and provided the molecular basis of one active compound as novel potential anticancer drug. Ó 2011 Elsevier Ltd. All rights reserved. Molecular targeted therapy is an efficient cancer treatment modality currently being widely investigated. Recently, Src homol- ogy-2 domain-containing protein tyrosine phosphatase (Shp2) was identified as a novel therapy target for several diseases, such as dia- betes, obesity, 1 and cancer. 2,3 Its PTPN11 gene was also regarded as a proto-oncogene based on its high percentage mutation (4–35%) in different leukemia types. 4 Shp2 is a non-receptor protein tyrosine phosphatase (PTP) widely expressed in humans. It contains two Src homolog homology-2 (SH2) domains at the N-terminus of the molecule and a catalytic domain at the C-terminal tail. 5 In general, Shp2 activity is suppressed by the interaction between its N-termi- nal SH2 and PTP domains. When Shp2 is activated by the receptor of the tyrosine kinase signal (epidermal growth factor, insulin, and insulin-like growth factor-1), the SH2 domain binds to the tyrosine residues of the receptor. 6–8 As a result, the PTP domain is released and triggers several cytoplasmic kinase cascade pathways, such as Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt. Most Shp2 mutations break the interaction between the N-terminal SH2 and PTP domains and cause the activated mutation of Shp2 in cancer. 9 Thus, the inhibitory substances of Shp2 are considered as potent drugs for cancer treatment via 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.09.023 ⇑ Corresponding authors. Tel.: +86 592 2187225; fax: +86 592 2181879. E-mail addresses: zhongxian@xmu.edu.cn (Z. Lu), haifeng@xmu.edu.cn (H. Chen).   These authors have equal contribution. Table 1 Inhibitory effects of compounds on PTPs Compounds IC 50 (lM) Shp2-PTP VHR HePTP Imperatorin >100 >100 >100 1 >100 >100 >100 2 27.3 ± 0.32 * 51.8 ± 0.11 # >100 3 >100 >100 >100 4 17.2 ± 0.12 ** >100 44.8 ± 0.25 ## 5 23.9 ± 0.50 ** 35.2 ± 0.08 # >100 6 >100 >100 >100 7 64.1 ± 0.28 * 98.2 ± 0.07 >100 8 >100 >100 >100 9 26.6 ± 0.17 ** >100 >100 10 >100 >100 >100 11 20.7 ± 0.60 ** 60.7 ± 0.17 # 82.5 ± 0.43 12 >100 >100 >100 13 >100 >100 >100 * P <0.05 compared with Shp2-PTP control. ** P <0.01 compared with Shp2-PTP control. # P <0.05 compared with VHR control. ## P <0.05 compared with HePTP control. Bioorganic & Medicinal Chemistry Letters 21 (2011) 6833–6837 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl