title: Identification of GNE-293, a potent and selective PI3Kδ inhibitor: navigating in vitro genotoxicity while improving potency and selectivity.
abstract: 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.
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, United States. bsafina@gene.com
authors.forename: Brian S
authors.initials: BS
authors.lastname: Safina
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.forename: Angelina
authors.initials: A
authors.lastname: Bisconte
authors.forename: Diane
authors.initials: D
authors.lastname: Carrera
authors.forename: Georgette
authors.initials: G
authors.lastname: Castanedo
authors.forename: Michael
authors.initials: M
authors.lastname: Flagella
authors.forename: Robert
authors.initials: R
authors.lastname: Heald
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Murray
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Steve
authors.initials: S
authors.lastname: Price
authors.forename: Karin
authors.initials: K
authors.lastname: Reif
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Seward
authors.forename: Binqing
authors.initials: B
authors.lastname: Wei
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
mesh_terms: D000818:Animals; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D062105:Molecular Docking Simulation; D009152:Mutagenicity Tests; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D003499:Cyclic S-Oxides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011687:Purines; C587784:GNE-293
keywords: B-cell inhibition; Genotox; HCA; MNT; PI3K isoform selectivity; PI3K δ