The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.

Fragment‐based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease‐relevant targets. Among the numerous screening techniques, fluorine‐detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high‐quality and diverse library containing nearly 4000 fragments and screening for target‐specific binders within days. At the core of the approach is a novel broadband relaxation‐edited NMR experiment that covers the entire chemical shift range of drug‐like 19F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets.

Fragment‐based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease‐relevant targets. Among the numerous screening techniques, fluorine‐detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high‐quality and diverse library containing nearly 4000 fragments and screening for target‐specific binders within days. At the core of the approach is a novel broadband relaxation‐edited NMR experiment that covers the entire chemical shift range of drug‐like 19F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets.

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[reaction: see text] The synthesis of an indole diazabicyclo[3.2.2]nonedione derivative was achieved in a few steps starting from L-tryptophan. Reduction with borane-THF complex leads to fragmentation of the bicycle and the stereoselective formation of an azepinoindole derivative was observed.