ABSTRACT
The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/chemistry , Immunologic Factors/chemistry , Pyrrolidines/chemistry , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Binding Sites , Class I Phosphatidylinositol 3-Kinases/metabolism , Disease Models, Animal , Dogs , Half-Life , Humans , Immunologic Factors/metabolism , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Lectins, C-Type/metabolism , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Proto-Oncogene Proteins c-akt/metabolism , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Rats , Rats, Wistar , Rhinitis, Allergic/drug therapy , Signal Transduction/drug effects , 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.
