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Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Novartis Inst. for Biomedical Research, Cambridge, MA (United States)
+ Show Author Affiliations
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)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1404997
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 2 Vol. 8; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (5)

Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays journal October 2017
Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics journal May 2019
Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies journal February 2018
Chromatin dynamics underlying latent responses to xenobiotics journal January 2018
An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors journal November 2018

Figures / Tables (8)

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Scheme 1(p. 3)figure Scheme 1
Table 2(p. 3)table Table 2
Table-1(p. 3)table Table-1
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Related Subjects

2-HG
3-pyrimidin-4-yloxazolidin-2-one
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Mutant IDH1 inhibitor
allosteric inhibition
chirality-defined potency
preclinical in vivo activity