The Substrate-Activity-Screening methodology applied to receptor tyrosine kinases: A proof-of-concept study

► Substrate-Activity-Screening is applied to a tyrosine kinase. ► The substrate efficiency of a tetrapeptide was optimized using a modular approach. ► Substrates were then converted into inhibitors by replacement of the tyrosine. ► A correlation between substrate SAR and inhibitor SAR was confirmed. ► We obtained a low single-digit micromolar substrate-site inhibitor of IGF-1R.