生物活性

• 描述Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. IDH1 serves a significant role in cytoplasmic NADPH production. Somatic mutations in IDH1 have recently been identified in multiple human cancers. Mutation at the site of R132 of IDH1 confer on this enzymes a new activity: catalysis of alpha-ketoglutarate (2-OG) to the (R)-enantiomer of 2-hydroxyglutarate (R-2HG). AG-120 is a selective inhibitor of R132 mutated IDH1. The inhibitory IC₅₀s of AG-120 against IDH1-R132 mutants IDH1-R132H, IDH1-R132C, IDH1-R132G, IDH1-R132L and IDH1-R132S were 12, 13, 8, 13, and 12 nM, respectively. The inhibitory IC₅₀s of AG-120 against IDH1-R132 mutated HT1080, COR-L105 and HCCC-9810 cells were 8, 15 and 12 nM, respectively^[2]. In IDH1-R132 mutated samples derived from AML patients, AG-120 reduced the level of intracellular 2-HG by 96% at the lowest tested dose (0.5 μM) and by 98.6% and 99.7%, respectively, at 1 and 5 μM. 5 μM AG-120 also enhanced ability of primary patient myeloblasts to form differentiated colonies in methylcellulose assays^[2]. In HT1080 xenografts established in nude mice, a single oral dose of AG-120 at 50 or 150 mg/kg reduced tumor 2-HG concentration with maximum inhibition of 92.0% and 95.2%, respectively, achieved at about 12h post dose^[2].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03013998	Previously Untreated Acute Mye... more >>loid Leukemia Collapse <<	Phase 1 Phase 2	Recruiting	December 2021	United States, Arizona ... more >> Mayo Clinic Arizona Recruiting Phoenix, Arizona, United States, 85054 Principal Investigator: Lisa Sproat, MD          United States, California UCLA Ronald Reagan Medical Center Recruiting Los Angeles, California, United States, 90095 Principal Investigator: Gary Schiller, MD          University of California, San Francisco Recruiting San Francisco, California, United States, 94143 Principal Investigator: Gabriel Mannis, MD          United States, Colorado University of Colorado Recruiting Denver, Colorado, United States, 80203 Principal Investigator: Dan Pollyea, MD          United States, Florida Mayo Clinic Florida Recruiting Jacksonville, Florida, United States, 32224 Principal Investigator: James Foran, MD          United States, Georgia Emory University Recruiting Atlanta, Georgia, United States, 30308 Principal Investigator: William Blum, MD          United States, Illinois University of Chicago Recruiting Chicago, Illinois, United States, 60637 Principal Investigator: Wendy Stock, MD          United States, Maryland University of Maryland Medical Center Recruiting Baltimore, Maryland, United States, 21201 Principal Investigator: Maria Baer, MD          United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Principal Investigator: Eytan M Stein, MD          United States, Ohio Ohio State University Recruiting Columbus, Ohio, United States, 43210 Principal Investigator: John C Byrd, MD          Principal Investigator: Alice Mims, MD          Principal Investigator: Alison R Walker, MD, MPH          United States, Oregon Oregon Health & Science University Recruiting Portland, Oregon, United States, 97239 Principal Investigator: Uma Borate, MD          United States, Texas University of Texas Southwestern Recruiting Dallas, Texas, United States, 75390 Principal Investigator: Prapti Patel, MD          United States, Utah Huntsman Cancer Institute, University of Utah Recruiting Salt Lake City, Utah, United States, 84112 Principal Investigator: Michael Deininger, MD, PhD Collapse <<
  NCT03564821	IDH1 Mutation Myeloid Neoplasm... more >>s Collapse <<	Phase 1	Not yet recruiting	July 31, 2024	United States, Massachusetts ... more >> Massachusetts General Hospital Not yet recruiting Boston, Massachusetts, United States, 02214 Contact: Amir T Fathi, MD    617-724-4000    afathi@partners.org    Principal Investigator: Amir T Fathi, MD Collapse <<
  NCT02831972	Healthy	Phase 1	Completed	-	United States, Arizona ... more >> Tempe, Arizona, United States, 85283 Collapse <<

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