Targeting SH2 Domains in Breast Cancer

Overview

Journal Future Med Chem

Specialties Chemistry
Pharmacy

Date 2014 Dec 16

PMID 25495984

Citations 34

Authors

Pietro Morlacchi

Fredika M Robertson

Jim Klostergaard

John S McMurray

Affiliations

Soon will be listed here.

Abstract

Breast cancer is among the most commonly diagnosed cancer types in women worldwide and is the second leading cause of cancer-related disease in the USA. SH2 domains recruit signaling proteins to phosphotyrosine residues on aberrantly activated growth factor and cytokine receptors and contribute to cancer cell cycling, metastasis, angiogenesis and so on. Herein we review phosphopeptide mimetic and small-molecule approaches targeting the SH2 domains of Grb2, Grb7 and STAT3 that inhibit their targets and reduce proliferation in in vitro breast cancer models. Only STAT3 inhibitors have been evaluated in in vivo models and have led to tumor reduction. Taken together, these studies suggest that targeting SH2 domains is an important approach to the treatment of breast cancer.

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References

Page B, Croucher D, Li Z, Haftchenary S, Jimenez-Zepeda V, Atkinson J . Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: promising agents against multiple myeloma. J Med Chem. 2013; 56(18):7190-200. DOI: 10.1021/jm3017255. View

Zhang X, Yue P, Page B, Li T, Zhao W, Namanja A . Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci U S A. 2012; 109(24):9623-8. PMC: 3386073. DOI: 10.1073/pnas.1121606109. View

Song H, Wang R, Wang S, Lin J . A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc Natl Acad Sci U S A. 2005; 102(13):4700-5. PMC: 555708. DOI: 10.1073/pnas.0409894102. View

Thompson J, Cubbon R, Cummings R, Wicker L, Frankshun R, Cunningham B . Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002; 12(8):1219-23. DOI: 10.1016/s0960-894x(02)00106-3. View

Burke T . Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents. Int J Pept Res Ther. 2009; 12(1):33-48. PMC: 2678932. DOI: 10.1007/s10989-006-9014-7. View

Pero S, Shukla G, Cookson M, Flemer Jr S, Krag D . Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells. Br J Cancer. 2007; 96(10):1520-5. PMC: 2359946. DOI: 10.1038/sj.bjc.6603732. View

Stahl N, Farruggella T, Boulton T, Zhong Z, Darnell Jr J, Yancopoulos G . Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995; 267(5202):1349-53. DOI: 10.1126/science.7871433. View

Lin N, Winer E . Advances in adjuvant endocrine therapy for postmenopausal women. J Clin Oncol. 2008; 26(5):798-805. DOI: 10.1200/JCO.2007.15.0946. View

Matsuno K, Masuda Y, Uehara Y, Sato H, Muroya A, Takahashi O . Identification of a New Series of STAT3 Inhibitors by Virtual Screening. ACS Med Chem Lett. 2014; 1(8):371-5. PMC: 4007973. DOI: 10.1021/ml1000273. View

10.

Ambaye N, Lim R, Clayton D, Gunzburg M, Price J, Pero S . Uptake of a cell permeable G7-18NATE contruct into cells and binding with the Grb-7-SH2 domain. Biopolymers. 2010; 96(2):181-8. DOI: 10.1002/bip.21403. View

11.

Bobkova E, Weber M, Xu Z, Zhang Y, Jung J, Blume-Jensen P . Discovery of PDK1 kinase inhibitors with a novel mechanism of action by ultrahigh throughput screening. J Biol Chem. 2010; 285(24):18838-46. PMC: 2881806. DOI: 10.1074/jbc.M109.089946. View

12.

Haftchenary S, Avadisian M, Gunning P . Inhibiting aberrant Stat3 function with molecular therapeutics: a progress report. Anticancer Drugs. 2010; 22(2):115-27. DOI: 10.1097/CAD.0b013e328341185b. View

13.

Pawson T . Protein modules and signalling networks. Nature. 1995; 373(6515):573-80. DOI: 10.1038/373573a0. View

14.

Huang S . Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res. 2007; 13(5):1362-6. DOI: 10.1158/1078-0432.CCR-06-2313. View

15.

Foulkes W, Smith I, Reis-Filho J . Triple-negative breast cancer. N Engl J Med. 2010; 363(20):1938-48. DOI: 10.1056/NEJMra1001389. View

16.

Waksman G, Kumaran S, Lubman O . SH2 domains: role, structure and implications for molecular medicine. Expert Rev Mol Med. 2004; 6(3):1-18. DOI: 10.1017/S1462399404007331. View

17.

Lee S, Ghosh S, Han H, Stone R, Bottsford-Miller J, Shen D . Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma. Clin Cancer Res. 2012; 18(15):4114-21. PMC: 3638880. DOI: 10.1158/1078-0432.CCR-11-3250. View

18.

Niu G, Wright K, Huang M, Song L, Haura E, Turkson J . Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002; 21(13):2000-8. DOI: 10.1038/sj.onc.1205260. View

19.

Mandal P, Heard P, Ren Z, Chen X, McMurray J . Solid-phase synthesis of Stat3 inhibitors incorporating O-carbamoylserine and O-carbamoylthreonine as glutamine mimics. Bioorg Med Chem Lett. 2006; 17(3):654-6. PMC: 2676682. DOI: 10.1016/j.bmcl.2006.10.099. View

20.

Miklossy G, Hilliard T, Turkson J . Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov. 2013; 12(8):611-29. PMC: 4038293. DOI: 10.1038/nrd4088. View