Scaffold hopping is a drug design strategy in which the core chemical structure of a drug candidate is replaced isosterically, which leads to structurally novel compounds. This strategy is commonly used in designing kinase inhibitors. All kinases have a conserved activation loop characterized by an Asp-Phe-Gly (DFG) motif. This motif exists in a “DFG-in” structural conformation, and a conformational change to a “DFG-out” structure that can no longer bind Mg²⁺ results in inactivation.

In this study, the researchers describe a strategy to generate an array of DFG-out conformation inhibitors with three different hinge-binders and two DFG-pocket groups. They systematically evaluated parts of DFG-out inactive conformation inhibitors that affect kinome-wide selectivity and identified elements that could be used as the starting point for targeting 36 distinct kinases. Next, they applied their strategy to Abl kinase to measure potency of selective inhibitors under “real-world” conditions using the NanoLuc®-Abl1 fusion expression vector and NanoBRET® Intracellular Target Engagement Assay. They also studied inhibitor binding to Axl kinase using a radiometric assay. Based on their results, the researchers identified two selective inhibitors that display low nanomolar potency against Axl or wild-type and clinically relevant mutants of Abl.

Keywords: kinase inhibitors, kinase target engagement, Abl, Axl

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