生物活性

• 描述Somatic point mutations in the active site of isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple tumors. Enasidenib is a potent and selective inhibitor of the mutant IDH2. It inhibits the production of oncometabolite (R)-2-hydroxyglutarate (2HG) by the IDH2^R140Q homodimer, the IDH2^R140Q/WT heterodimer, and the IDH2^R172K/WT heterodimer with IC50 values of 0.1, 0.03, and 0.01μM, respectively. Enasidenib also displayed time-dependent potency for inhibiting the canonical forward (oxidative) reaction in the IDH2^WT homodimer with an IC50 value of 1.8μM. Moreover, Enasidenib inhibited 2HG production in HCT-116 KI (IDH2^R172K, TF-1 pLVX (IDH2^R140Q), TF-1 pLVX (IDH2^R172K), U87MG pLVX (IDH2^R172K), U87MG pLVX (IDH2^R140Q) cell lines with IC50 values of 0.53, 0.02, 0.98, 1.59, and 0.01μM, respectively. In the presence of 0.1μM enasidenib, IDH2^R140Q cells exhibited an approximately 50% decrease in intracellular 2HG and an increase in the percentage of cells expressing cell surface markers associated with granulocytic differentiation. Incubation of IDH2^R140Q blast cells with 5μM enasidenib for 8 days significantly increased the number of cells with multilobed nuclei when compared with control cells. In tumor-bearing mice, two doses of 25 mg/kg enasidenib given 12h apart resulted in 99.2% inhibition of 2HG production in tumors. In a mouse xenograft model of primary human AML, administration of enasidenib (30 mg/kg, twice daily) for 38 days reduced serum and intracellular 2HG levels compared to vehicle-treated group^[2].
• 作用机制AG-221 inhibits IDH2 by allosterically stabilizing its open homodimer conformation, thereby preventing the conformational change required for catalysis^[2].

• 动物研究
  剂量	Mice: 5 mg/kg - 45 mg/kg[3] (p.o.)
  给药途径	p.o.

• 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
  NCT02577406	Leukemia, Myeloid ... more >> Isocitrate Dehydrogenase Collapse <<	Phase 3	Recruiting	July 28, 2022	-
  NCT03680677	Leukemia, Acute ... more >> MDS Collapse <<	Not Applicable	Not yet recruiting	November 2025	United States, Pennsylvania ... more >> Abramson Cancer Center of the University of Pennsylvania Not yet recruiting Philadelphia, Pennsylvania, United States, 19104 Collapse <<
  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 <<

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