Identification of GNE-293, a potent and selective PI3Kδ inhibitor: Navigating in vitro genotoxicity while improving potency and selectivity

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 17; pp. 4953 - 4959
• Main Authors: Safina, Brian S., Sweeney, Zachary K., Li, Jun, Chan, Bryan K., Bisconte, Angelina, Carrera, Diane, Castanedo, Georgette, Flagella, Michael, Heald, Robert, Lewis, Cristina, Murray, Jeremy M., Nonomiya, Jim, Pang, Jodie, Price, Steve, Reif, Karin, Salphati, Laurent, Seward, Eileen M., Wei, Binqing, Sutherlin, Daniel P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2013
• Subjects: Animals; B-cell inhibition; Cell Line; chemistry; Cyclic S-Oxides - chemistry; Cyclic S-Oxides - pharmacology; Dogs; Genotox; genotoxicity; HCA; Humans; in vitro studies; MNT; Molecular Docking Simulation; Mutagenicity Tests; pharmacokinetics; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3K isoform selectivity; PI3K δ; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - toxicity; Purines - chemistry; Purines - pharmacology; Rats; Structure-Activity Relationship; Genotox; MNT; PI3K isoform selectivity; PI3K δ; B-cell inhibition; HCA
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.052

In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ’s Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile.