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Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
- Source :
- ACS medicinal chemistry letters. 8(10)
- Publication Year :
- 2017
-
Abstract
- Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, 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. 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.
- Subjects :
- 0301 basic medicine
IDH1
Organic Chemistry
Mutant
Allosteric regulation
Treatment options
Pharmacology
Biology
Biochemistry
Clinical trial
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
In vivo
030220 oncology & carcinogenesis
Drug Discovery
Hotspot mutation
Tumor xenograft
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 8
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- ACS medicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....2ce7a354b7b8d1eb03e1a80dbd9cdf7a