Rational Optimization of Tumor Suppressor ‐Derived Peptide Inhibitor Selectivity between Oncogene Tyrosine Kinases ErbB1 and ErbB2

The tumor‐suppressor protein Mig‐6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2. Despite their highly homologous nature, these two kinases are separately involved in the development of different types of human cancer. Here, we utilized a rational strategy to iteratively optimize the interaction specificity of the two kinases with a Mig‐6 derived peptide by exploiting structural diversity space. Instead of traditionally improving the peptide binding potency, the optimization attempts to maximize the affinity difference between peptides binding to ErbB1 and ErbB2. The computational design was also substantiated by using fluorescence‐based assays. Consequently, we successfully designed three peptides, HSLTPTQSF, THLMNLLRI, and NSGCPMHK, with high or moderate selectivity for ErbB1 over ErbB2 (3.1‐, 6.3‐, and 3.0‐fold, respectively) and two peptides, PCMTDFLFT and WVIFPSQTN, with moderate or modest selectivity for ErbB2 over ErbB1 (3.5‐ and 1.6‐fold, respectively). The method is expected to be used for the rational molecular design of selective peptide entities for other protein systems. The tumor suppressor Mig‐6‐derived peptide selectivity between the human receptor tyrosine kinases ErbB1 and ErbB2 was improved by using an iteration optimization algorithm. The optimization attempts to maximize the affinity difference between peptide binding to ErbB1 and ErbB2. A number of peptides were successfully ...
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Full Paper Source Type: research