Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3 '-substituted tyrosine derivatives
文献类型：期刊论文
| 作者 | Song, YL; Peach, ML; Roller, PP; Qiu, S; Wang, SM; Long, YQ |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2006-03-09 |
| 卷号 | 49期号:5页码:1585-1596 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm050910x |
| 文献子类 | Article |
| 英文摘要 | The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. An impressive number of synthetic Grb2-SH2 domain inhibitors have been identified; however, clinical agents operating by this mechanism are lacking, due in part to the unique requirement of anionic phosphate-mimicking functionality for high SH2 domain-binding affinity or the extended peptide nature of most inhibitors. In the current study, a new binding motif was successfully developed by the incorporation of 3'-substituted tyrosine derivatives into a simplified nonphosphorylated cyclic pentapeptide scaffold (4), which resulted in high affinity Grb2-SH2 inhibitors without any phosphotyrosine or phosphotyrosine mimetics. The new L-amino acid analogues hearing an additional nitro, amino, hydroxy, methoxy or carboxy group at the 3'-position of the phenol ring of tyrosine were prepared in an orthogonally protected form suitable for solid-phase peptide synthesis using Fmoc protocols. The incorporation of these residues into cyclic peptides composed of a five-amino acid sequence motif, Xx(1)-Leu-(3'-substituted-Tyr)-Ac6c-Asn, provided a brand new class of nonphosphorylated Grb2 SH2 domain inhibitors with reduced size, charge and peptidic character. The highest binding affinity was exhibited by the 3'-aminotyrosine (3'-NH2-Tyr)-containing (R)-sulfoxide-cyclized pentapeptide (10b) with an IC50 = 58 nM, the first example with low-nanomolar affinity for a five-amino acid long sequence binding to Grb2-SH2 domain free of any phosphotyrosine or phosphotyrosine mimics. However, the incorporation of 3'-NO2-Tyr, 3'-OH-Tyr or 3'-OCH3-Tyr surrogates in the pentapeptide scaffold is detrimental to Grb2-SH2 binding. These observations were rationalized using molecular modeling. More significantly, the best Grb2-SH2 inhibitor 10b showed excellent activity in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with an IC50 value of 19 nM. This study is the first attempt to identify novel nonphosphorylated high affinity Grb2 SH2 inhibitors by the utilization of 3'-substituted tyrosine derivatives, providing a promising new strategy and template for the development of non-pTyr-containing Grb2-SH2 domain antagonists with potent cellular activity, which potentially may find value in chemical therapeutics for erbB2-related cancers. |
| WOS关键词 | CYCLIC PEPTIDE ANTAGONISTS ; STRUCTURE-BASED DESIGN ; L-DOPA DERIVATIVES ; SH2 DOMAIN ; SIGNAL-TRANSDUCTION ; BINDING AFFINITY ; STRUCTURAL BASIS ; BREAST-CANCER ; INHIBITORS ; SPECIFICITY |
| 资助项目 | NCI NIH HHS[N01-CO-12400] ; Intramural NIH HHS[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000236005400011 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273650]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Long, YQ |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Inst Biol Sci,Grad Sch, Shanghai 201203, Peoples R China 2.NCI Frederick, SAIC, Basic Res Program, Ft Detrick, MD 21702 USA 3.NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA 4.Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Ann Arbor, MI 48109 USA 5.Univ Michigan, Ctr Comprehens Canc, Dept Med Chem, Ann Arbor, MI 48109 USA |
| 推荐引用方式 GB/T 7714 | Song, YL,Peach, ML,Roller, PP,et al. Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3 '-substituted tyrosine derivatives[J]. JOURNAL OF MEDICINAL CHEMISTRY,2006,49(5):1585-1596. |
| APA | Song, YL,Peach, ML,Roller, PP,Qiu, S,Wang, SM,&Long, YQ.(2006).Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3 '-substituted tyrosine derivatives.JOURNAL OF MEDICINAL CHEMISTRY,49(5),1585-1596. |
| MLA | Song, YL,et al."Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3 '-substituted tyrosine derivatives".JOURNAL OF MEDICINAL CHEMISTRY 49.5(2006):1585-1596. |
入库方式： OAI收割
来源：上海药物研究所
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