Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 9, Issue 7, Pages 746-751Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00182
Keywords
Mutant IDH1; inhibition of 2-HG production; in vivo anticancer activity; brain penetration; clinical candidate
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Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1(R1321H). This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG.
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