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

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.049 Diseases
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 151-156 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260722
• Chủ đề: 1. 2-hg; 2. 37 inorganic, organic, physical, and analytical chemistrysciences; 3. 3-pyrimidin-4-yloxazolidin-2-one; 4. 60 applied life sciences; 5. Allosteric inhibition; 6. Chirality-defined potency; 7. Mutant idh1 inhibitor; 8. Preclinical in vivo activity

Tóm tắt

 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 IDH1<
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 . 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.