Development and Evaluation of Novel Phosphotyrosine Mimetic Inhibitors Targeting the Src Homology 2 Domain of Signaling Lymphocytic Activation Molecule (SLAM) Associated Protein

详细信息    查看全文

• 作者：Chi-Yuan Chu ; Chun-Ping Chang ; Yun-Ting Chou ; Handoko ; Yi-Ling Hu ; Lee-Chiang Lo ; Jing-Jer Lin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：2841-2849
• 全文大小：441K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins. A plate-based assay was also established to screen for inhibitors that disrupt the interaction between a phosphopeptide of SLAM (signaling lymphocytic activation molecule) and its interacting protein SAP (SLAM-associated protein). We identified a number of inhibitors with IC₅₀ values in the range of 17鈥?5 渭M, implying that the cycloSal phosphodiester-carrying amino acid could mimic the phosphotyrosyl residue. Our results also raise the possibility of integrating the newly developed phosphotyrosine mimetic moiety into inhibitors designed for other SH2 domain-containing proteins.