Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 614.1 Forensic medicine
• 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, 2017
• Mô tả vật lý: Size: p. 1116-1121 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260376
• Chủ đề: 1. 60 applied life sciences; 2. Brain penetration; 3. Clinical candidate; 4. In vivo anticancer activity; 5. Inhibition of 2-hg production; 6. Mutant idh1

Tóm tắt

 Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg<
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 . Having identified an allosteric, induced pocket of IDH1<
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 , we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. We report preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.