title: Discovery of novel PI3-kinase δ specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition.
abstract: PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States. bsafina@gene.com
authors.forename: Brian S
authors.initials: BS
authors.lastname: Safina
authors.forename: Stewart
authors.initials: S
authors.lastname: Baker
authors.forename: Matt
authors.initials: M
authors.lastname: Baumgardner
authors.forename: Paul M
authors.initials: PM
authors.lastname: Blaney
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Cartwright
authors.forename: Georgette
authors.initials: G
authors.lastname: Castanedo
authors.forename: Christine
authors.initials: C
authors.lastname: Chabot
authors.forename: Arnaud J
authors.initials: AJ
authors.lastname: Cheguillaume
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Bindu
authors.initials: B
authors.lastname: Goyal
authors.forename: Timothy
authors.initials: T
authors.lastname: Hancox
authors.forename: Raj K
authors.initials: RK
authors.lastname: Handa
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Iyer
authors.forename: Jasmit
authors.initials: J
authors.lastname: Kaur
authors.forename: Rama
authors.initials: R
authors.lastname: Kondru
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.forename: Sussie L
authors.initials: SL
authors.lastname: Krintel
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lucas
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Sophie
authors.initials: S
authors.lastname: Mukadam
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Nadin
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Fernando
authors.initials: F
authors.lastname: Padilla
authors.forename: Wylie S
authors.initials: WS
authors.lastname: Palmer
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Neil
authors.initials: N
authors.lastname: Pegg
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: Pascal A
authors.initials: PA
authors.lastname: Savy
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Seward
authors.forename: Stephen
authors.initials: S
authors.lastname: Shuttleworth
authors.forename: Sukhjit
authors.initials: S
authors.lastname: Sohal
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.forename: Parcharee
authors.initials: P
authors.lastname: Tivitmahaisoon
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Binqing
authors.initials: B
authors.lastname: Wei
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.forename: Chenghong
authors.initials: C
authors.lastname: Zhang
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C031000:benzimidazole; C510163:CYP3A4 protein, human