<br/>Phosphoinositide 3-kinase δ (PI3Kδ) is a promising therapeutic target for the treatment of inflammatory and respiratory diseases. The recent emergence of several inhaled and oral PI3Kδ inhibitors and their ongoing clinical investigations requires a better understanding of the behaviour of small PI3Kδ inhibitors, especially in the lung following inhalation where there is relatively limited information on optimal drug localization and lung retention. New tools/capabilities that can help to relate molecular properties to cellular/tissue disposition will be of considerable value. This programme of research describes the first PI3Kδ chemical probes designed for bioorthogonal chemistry applications. The compounds were developed using a structure-based design approach by tagging PI3Kδ inhibitors with a <i>trans</i>-cyclooctene (TCO) tag. The chemical probes were subsequently profiled in a cellular imaging and target engagement assays involving an inverse electron demand Diels-Alder reaction with a tetrazine-tagged fluorescent dye (Figure 1). The PI3Kδ chemical probes successfully enabled the evaluation of the potential differences in compound localisation within the cell that may help to relate the molecular properties of inhaled PI3Kδ to their lung distribution. A chemical probe derived from an oral PI3Kδ inhibitor also successfully enabled the cellular target engagement measurement of non-tagged PI3Kδ inhibitors. These PI3Kδ chemical probes are useful biological tools that allow the further study of this target and help to link biodistribution to molecular properties in order to more accurately predict the behaviour of inhaled compounds in the future.

Bioorthogonal chemistry approaches to the cellular imaging of PI3Kδ inhibitors

2019 Fall National Meeting

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