PI3Kδ is a lipid kinase involved in key immune cell signaling pathways and functions. In 2014, the selective inhibition of PI3Kδ achieved clinical proof of concept with the approval of Idelalisib as a first-in-class PI3Kδ inhibitor for the treatment of hematologic malignancies such as relapsed B-cell chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). We have previously disclosed the discovery of a selective and efficient purine PI3Kδ inhibitor (MSD-496486311) bearing a methylpyrimidine in the 8-position and an aminopyrrolidine in the 6-position; the latter positions an amide substituent to form a key, selectivity-inducing interaction with Trp760 of PI3Kδ. In this presentation, we will describe our efforts to further enhance the potency and selectivity of our purine-based PI3Kδ inhibitors through the development of partially saturated, heterobicyclic inhibitors designed to lock the compounds in the bioactive conformation. Guided by the crystal structure of our lead compound, we identified series of substituted triazolo-, pyrazolo- and imidazo-fused bicyclic amino purine compounds with promising PI3Kδ potency and selectivity. We will also detail our synthetic route to these novel heterocycles, as well as the optimization of global physical properties to address preclinical species clearance and half-life. Optimized inhibitors possessed excellent whole blood potency, selectivity, and half-life profiles, suitable for a low predicted human dose.

Discovery and optimization of fused heterobicyclic amino purine as potent and selective PI3Kδ inhibitors

ACS Fall 2021

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