title: Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.
abstract: High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125,1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinoneIDH889(5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Levell
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Caferro
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Gregg
authors.initials: G
authors.lastname: Chenail
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ina
authors.initials: I
authors.lastname: Dix
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Dooley
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Brant
authors.initials: B
authors.lastname: Firestone
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Fortin
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Giraldes
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ty
authors.initials: T
authors.lastname: Gould
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Growney
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jones
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Raviraj
authors.initials: R
authors.lastname: Kulathila
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Fallon
authors.initials: F
authors.lastname: Lin
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Arne
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: van der Plas
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Slocum
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Troy
authors.initials: T
authors.lastname: Smith
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Remi
authors.initials: R
authors.lastname: Terranova
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: B Barry
authors.initials: BB
authors.lastname: Touré
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Viraj
authors.initials: V
authors.lastname: Tyagi
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Fan S
authors.initials: FS
authors.lastname: Yang
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Liping X
authors.initials: LX
authors.lastname: Zhou
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Cho
keywords: 2-HG; 3-pyrimidin-4-yloxazolidin-2-one; Mutant IDH1 inhibitor; allosteric inhibition; chirality-defined potency; preclinical in vivo activity