Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein.

Chi-Yuan Chu, Chun-Ping Chang, Yun-Ting Chou, Handoko, Yi-Ling Hu, Lee-Chiang Lo, Jing-Jer Lin

Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.

Journal of medicinal chemistry 2013 Apr 11

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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 17-35 μM, 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.

Citation

Chi-Yuan Chu, Chun-Ping Chang, Yun-Ting Chou, Handoko, Yi-Ling Hu, Lee-Chiang Lo, Jing-Jer Lin. Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein. Journal of medicinal chemistry. 2013 Apr 11;56(7):2841-9