ABSTRACT
PI3Kδ mediates key immune cell signaling pathways and is a target of interest for multiple indications in immunology and oncology. Here we report a structure-based scaffold-hopping strategy for the design of chemically diverse PI3Kδ inhibitors. Using this strategy, we identified several scaffolds that can be combined to generate new PI3Kδ inhibitors with high potency and isoform selectivity. In particular, an oxindole-based scaffold was found to impart exquisite selectivity when combined with several hinge binding motifs.
Subject(s)
Drug Design , Oxindoles/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Binding Sites/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Structure , Oxindoles/chemical synthesis , Oxindoles/chemistry , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.
Subject(s)
Class Ia Phosphatidylinositol 3-Kinase/metabolism , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Pyrrolidines/pharmacology , Animals , Dogs , Drug Design , HeLa Cells , Humans , Male , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/toxicity , Purines/chemical synthesis , Purines/toxicity , Pyrrolidines/chemical synthesis , Pyrrolidines/toxicity , Rats, WistarABSTRACT
The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.
