Dysfunctional regulation of the PI3K pathway results in a variety of disease states, including several cancers, autoimmune disorders, and inflammation. Class I PI3Ks comprise four isoforms: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Identification of PI3K inhibitors with differential isoform selectivity profiles may be advantageous in the treatment of specific diseases, with the potential for fewer adverse effects. The propeller shape of PI3K inhibitors such as idelalisib imparts PI3Kδ selectivity. This presentation will describe the discovery of two propeller-shaped compounds with distinct selectivity profiles. Highly selective PI3Kδ inhibitor GS-9901 demonstrates improved metabolic stability, PK suitable for once-daily dosing, and is efficacious in a rodent model of rheumatoid arthritis. In contrast, dual PI3K β/δ inhibitor GS-9944 interacts with a unique residue in the catalytic pocket imparting PI3Kβ activity. GS-9944 displays excellent pharmacokinetic properties and demonstrates efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

Discovery of isoform-selective inhibitors of PI3K in a series of propeller-shaped compounds

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.