Therapeutic Targeting of Oncogenic Tyrosine Phosphatases Rochelle Frankson, Zhi-Hong Yu, Yunpeng Bai, Qinglin Li, Ruo-Yu Zhang, and Zhong-Yin Zhang
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Published OnlineFirst August 30, 2017; DOI: 10.1158/0008-5472.CAN-17-1510 Cancer Review Research Therapeutic Targeting of Oncogenic Tyrosine Phosphatases Rochelle Frankson, Zhi-Hong Yu, Yunpeng Bai, Qinglin Li, Ruo-Yu Zhang, and Zhong-Yin Zhang Abstract Protein tyrosine phosphatases (PTP) are exciting and novel metabolic syndromes, and autoimmune diseases. The Src homol- targets for cancer drug discovery that work in concert with protein ogy domain containing phosphatase 2 (SHP2) and the three- tyrosine kinases (PTK) in controlling cellular homeostasis. Given membered family of phosphatases of regenerating liver (PRL) are the activating role that some PTKs play in initiating growth factor– infamously oncogenic members of the PTP superfamily. Both are mediated cellular processes, PTPs are usually perceived as the established regulators of major cancer pathways such as Ras/ negative regulators of these events and therefore tumor suppres- ERK1/2, Src, JAK/STAT, JNK, NF-kB, and PTEN/PI3K/AKT. Fur- sive in nature. However, mounting evidence indicate that PTPs do thermore, upregulation, mutation, or other dysregulation of these not always antagonize the activity of PTKs in regulating tyrosine PTPs has been positively correlated with cancer initiation and phosphorylation, but can also play dominant roles in the initi- progression. This review will provide topical coverage of target ation and progression of signaling cascades that regulate cell validation and drug discovery efforts made in targeting these functions. It follows, therefore, that PTP malfunction can actively oncogenic PTPs as compelling candidates for cancer therapy. contribute to a host of human disorders, in particular, cancer, Cancer Res; 77(21); 1–5. Ó2017 AACR. Introduction include a better coverage of PTP function and target validation. In turn, this has generated heightened interest over their candidacy Protein tyrosine phosphorylation is essential for regulating a for therapeutic development. Previously insurmountable obsta- myriad of cellular processes, including cell growth and survival. cles such as inhibitor potency, specificity and bioavailability are Dysregulation of tyrosine phosphorylation mediated cell signal- being addressed by methods of drug design that exploit unique ing is a well-recognized cause for diseases. Numerous medicinal structural features proximal to the catalytic and regulatory sites. agents acting on protein tyrosine kinases (PTK) have reached This review aims to shine the spotlight on two oncogenic PTPs: the the clinic in recent years. Because protein tyrosine phosphoryla- Src homology 2 domain containing phosphatase 2 (SHP2) and tion is a dynamic and reversible posttranslational modification the phosphatases of regenerating liver (PRL). SHP2 and PRLs play that is orchestrated by a regulatory partnership between PTKs and critical roles in cancer progression and are emerging as compelling protein tyrosine phosphatases (PTP), there is the potential to therapeutic targets for cancer drug discovery. modulate disease progression by targeting the PTPs. Indeed, malfunction of PTP activity contributes to the development and SHP2 Is a Bona Fide Oncoprotein progression of aberrations such as cancer, metabolic and auto- immune disorders, infectious disease and neurodegeneration. SHP2, encoded by the PTPN11 gene, is an allosteric phospha- Given the involvement of PTPs to human malady, a more com- tase containing two SH2 domains (i.e., N-SH2 and C-SH2), a PTP prehensive investigation of them is paramount to the develop- catalytic domain and a C-terminal tail (Fig. 1A). In the basal state, ment of more effective therapeutic interventions. In this review, SHP2 is kept in an autoinhibited conformation by intramolecular we will focus on the PTPs and their eligibility as targets of drug interactions between the N-SH2 domain and the catalytic cleft of discovery in cancer. Although several PTPs have been implicated the PTP domain (2). However, upon growth factor or cytokine as potential tumor suppressors, growing evidence establish that a stimulation, binding of specific pTyr motifs from growth factor large number of PTPs function as powerful tumor promoters in receptors or adaptor proteins to the N-SH2 domain releases many types of cancers (1). Over the years, our understanding of autoinhibition and activates SHP2 (Fig. 1A). This elegant allo- how PTPs contribute to signaling and disease has expanded to steric mechanism ensures that SHP2 exerts its phosphatase activity only when recruited to appropriate cellular locales (3). SHP2 is required for full activation of the Ras/ERK1/2 pathway, a major Departments of Medicinal Chemistry and Molecular Pharmacology and Chem- signaling cascade in cancer biology. Although there is general istry, Center for Cancer Research and Institute for Drug Discovery, Purdue agreement that SHP2 acts downstream of growth factor receptors University, West Lafayette, Indiana. and upstream of Ras, the mechanistic underpinnings of how Corresponding Author: Zhong-Yin Zhang, Purdue University, 575 Stadium Mall SHP2 mediates Ras/ERK1/2 activation remains an active area Drive, RHPH 202A, West Lafayette, IN 47907. Phone: 765-496-3720; Fax: 765- of research. Current models suggest that SHP2 fulfills its positive 494-1414; E-mail: [email protected] role in signaling by dephosphorylating pTyr residues, such as doi: 10.1158/0008-5472.CAN-17-1510 the RasGAP-binding site on receptor tyrosine kinases, the CSK- Ó2017 American Association for Cancer Research. binding sites on paxillin and PAG/CBP, or the Grb2/SOS binding www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 30, 2017; DOI: 10.1158/0008-5472.CAN-17-1510 Frankson et al. AB Growth factor Growth factor Allosteric Active site directed inhibitors inhibitor CI N O IIB-08 RTK RTK CI NO2 NH HO 2 N O N HN NH N HO N HO3S N N N N N O O H GS-493 Cbp NH 2 N N N PP Sprouty PP SHP099 H P CSK HO I O P NO2 HO 11a-1 S SHP2 Src SHP2 O P CSK PP P PP Stablize RAS autoinhibited Paxillin conformation Block active site RAF PI3K JAK2 Activated by pTyr PP PP N-SH2 RasGAP motif in RTKs/scaffold pY pY MEK C-SH2 proteins PTP N-SH2 C-SH2 PTP C-tail κ C-tail JNKERK1/2 AKT NF- B STAT Cell proliferation, differentiation, survival CD Growth factor Active site Antibodies directed inhibitors RTK CNNMs O NH Trimer S disrupter NH PP 2 PTEN PRL Src Thienopyridone PRL PRL N O N O HO NH PP N O Br O 2+ OH PI3K AKT p115 RhoGAP ERK1/2 [Mg ] O Analog 3 PRL Cmpd-43 PP EMT, cell proliferation, migration, tumor progression © 2017 American Association for Cancer Research Figure 1. Signaling mechanisms and therapeutic targeting of SHP2 and PRLs. A, The schematic structure of SHP2, strategies of targeting SHP2 for cancer therapy, and the latest small-molecule SHP2 inhibitors. B, SHP2 promotes multiple oncogenic signaling pathways. C, PRL-mediated signaling in cancer. D, Strategies of targeting PRLs for cancer therapy and representative PRL inhibitors. EMT, epithelial–mesenchymal transition. site on Sprouty1 (Fig. 1B), which negatively regulate Ras/ERK1/2 also show that the leukemia associated PTPN11 E76K mutation in pathway activation (4). Most recent data indicate that dephos- the bone marrow microenvironment promotes the development phorylation of Ras/pTyr32 by SHP2 can also lead to Ras activation and progression of myeloproliferative neoplasm (8). Although (5). In addition to the Ras/ERK1/2 pathway, SHP2 has also been PTPN11 mutations are less frequently observed in solid tumors shown to promote PI3K/AKT, JAK/STAT, JNK, and NF-kB signal- than in leukemia, SHP2 overexpression is common in many types ing (Fig. 1B), which are strongly associated with various human of carcinoma. For example, SHP2 is overexpressed in approxi- þ þ cancers (3, 4, 6). mately 80% of HER2 ERa⁄PR infiltrating ductal carcinoma, and Genetic and clinical studies have linked SHP2 with many elevated SHP2 level in breast cancer tissues is positively correlated human diseases including cancers. Germline gain-of-function with lymph node metastasis and higher tumor grade (9). Fur- PTPN11 mutations cause approximately 40% to 50% of Noonan thermore, SHP2 signature genes are overexpressed in approxi- syndrome, an autosomal dominant developmental disorder with mately 55% of human primary breast tumors and correlated with increased risk of malignancy. Somatic gain-of-function PTPN11 invasive ductal carcinoma and poor prognosis (10). In addition, mutations are broadly associated with leukemia (including juve- SHP2 is positively correlated with EGFR expression in breast nile myelomonocytic leukemia) and various solid tumors includ- cancers (11), consistent with the obligatory requirement of SHP2 ing lung adenocarcinoma, colon cancer, neuroblastoma, mela- in receptor tyrosine kinase signaling. SHP2 is also upregulated in noma and hepatocellular carcinoma (4, 6, 7). Recent evidence human prostate cancer and positively correlates with advanced OF2 Cancer Res; 77(21) November 1, 2017 Cancer Research Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 30, 2017; DOI: 10.1158/0008-5472.CAN-17-1510 Phosphatases as Targets for Cancer Drug Discovery disease stage, tumor metastasis and shortened patient survival obtained with SHP2 inhibitors of diverse structural scaffolds and (12). In fact, increased SHP2 expression is also found in gastric, distinct mode of action strongly