生物活性

• 描述IDO1 (Indoleamine 2,3-dioxygenase-1) is a heme-containing monomeric oxidoreductase, which can catalyze the degradation of the essential amino acid tryptophan to N-formyl-kynurenine, an intermediate metabolized through a series of steps to form NAD⁺. IDO1 is considered to play an important role in the induction of tumor immune tolerance, which can regulate the immunosuppressive mechanisms responsible for tumor escape from host immune surveillance. PF-06840003 is a selective IDO1 inhibitor with IC50 values of 0.41μM, 0.59μM and 1.5μM for hIDO-1, dIDO-1 and mIDO-1 (measured by enzymic acitivity), respectively. PF-06840003 is a racemic mixture, of which only the R-isomer is active, in development due to rapid epimerization of the chiral carbon that is adjacent to a carbonyl group. Incubation with PF-06840003 for 24h also showed significant inhibition on kynurenine production in HeLa, THP and human whole blood cells induced by INFγ or LPS^[1], and reversed intratumoral KYN levels by >80% in vivo^[2]. Oral administration of the PF-06840003 achieved total brain to plasma Kp ratio 0.51, indicating the brain penetrance of this compound^[1]. Combination of PF-06840003 with immunotherapies including antibodies against PD-1 showed inhibition of tumor growth in multiple mouse syngeneic models^[2].
• 作用机制PF-06840003 forms H-bond interaction with the propionate of the heme, not the heme iron atom, which is differently from most of the IDO-1 inhibitors described so far.^[1]

• 动物研究
  剂量	Mice[2] (p.o.): 20 mg/kg - 1200mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 3 mg/kg 3 mg/kg 3 mg/kg Administration p.o. p.o. p.o. F 0.593 0.94 0.186 AUCinf 2170 ng·h/ml 6940 ng·h/ml 237 ng·h/ml T1/2 2.48 h 2.42 h 0.84 h Tmax 0.58 h 1.3 h 0.25 h Cmax 538 ng/ml 985 ng/ml 219 ng/ml

• 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
  NCT02764151	Oligodendroglioma ... more >> Astrocytoma Malignant Glioma Collapse <<	Phase 1	Active, not recruiting	December 26, 2018	United States, California ... more >> Ronald Reagan UCLA Medical Center, Drug Information Center Los Angeles, California, United States, 90095-6894 Ronald Reagan UCLA Medical Center Los Angeles, California, United States, 90095-6894 UCLA Clinical & Translational Research Center Los Angeles, California, United States, 90095 UCLA Oncology Center Los Angeles, California, United States, 90095 UCLA School of Medicine Los Angeles, California, United States, 90095 United States, Massachusetts Massachusetts General Hospital Boston, Massachusetts, United States, 02114 Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02215 United States, New Mexico University of New Mexico Comprehensive Cancer Center Albuquerque, New Mexico, United States, 87102 United States, New York Columbia University Medical Center New York, New York, United States, 10019 Columbia University Medical Center New York, New York, United States, 10032 CUMC Research Pharmacy New York, New York, United States, 10032 Columbia Doctors Tarrytown Tarrytown, New York, United States, 10591 United States, North Carolina Duke Cancer Center Durham, North Carolina, United States, 27710 Duke University Medical Center, Duke Cancer Center Durham, North Carolina, United States, 27710 Collapse <<