| Literature DB >> 30034612 |
Qian Zhao1, James R Manning1, James Sutton1, Abran Costales1, Martin Sendzik1,2, Cynthia M Shafer1, Julian R Levell2, Gang Liu2, Thomas Caferro2, Young Shin Cho2, Mark Palermo2, Gregg Chenail2, Julia Dooley2, Brian Villalba2, Ali Farsidjani2, Jinyun Chen2, Stephanie Dodd2, Ty Gould2, Guiqing Liang2, Kelly Slocum2, Minying Pu2, Brant Firestone2, Joseph Growney2, Tycho Heimbach2, Raymond Pagliarini2.
Abstract
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 IDH1R132H. 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.Entities:
Year: 2018 PMID： 30034612 PMCID： PMC6047033 DOI： 10.1021/acsmedchemlett.8b00182
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345