生物活性

• 靶点	PI3Kγ IC50:16nM

• 描述PI3Ks are divided into three classes (I, II, and III) based on substrate specificity, sequence homology, and types of regulatory subunits. Class I PI3Ks are further divided into Class IA and Class IB. Class IB of PI3Ks containing the only member, PI3Kγ, is activated primarily by G-protein coupled receptors. The PI3Kγ isoform is mainly expressed in immune cells. Preclinical studies suggest that PI3Kγ inhibition in tumor-associated myeloid cells may be effective to prevent tumor growth. IPI-549 is a potent inhibitor of PI3Kγ (IC50 = 16 nM, measured by Promega ADP-Glo Max assay kit) with >100-fold selectivity over other lipid and protein kinases. IPI-549 shows excellent PI3Kγ potency (IC50 = 1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold) measured by cellular phospho-AKT inhibition assays in SKOV-3, 786-O, RAW 264.7, and RAJI cells. Also, IPI-549 inhibited PI3Kγ-dependent BMDM migration in a dose-dependent manner in vitro. 0.1 - 3 mg/kg oral treatment of IPI-549 significantly reduced neutrophil migration in a dose-dependent manner while a significant inhibition of PI3Kγ can be observed in the mouse air pouch model. IPI-549 is currently in Phase 1 clinical evaluation of advanced solid tumors^[1].

• 动物研究
  剂量	Mice: 15 mg/kg[2] (p.o.), 3 mg/kg[3] (i.p.)
  给药途径	p.o, i.p.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Monkeys[1] Dose 1 mg/kg 1 mg/kg 0.5 mg/kg 0.5 mg/kg Administration i.v. i.v. i.v. i.v. T1/2 3.2 h 4.4 h 6.7 h 4.3 h Vss 0.8 L/kg 1.2 L/kg 1.3 L/kg 1.3 L/kg CL 3.6 ml/min/kg 4.4 ml/min/kg 2.8 ml/min/kg 4.3 ml/min/kg F 0.88 0.57 0.65 0.31

• 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
  NCT02637531	Advanced Solid Tumors (Part A/... more >>B/C/D) Non-small Cell Lung Cancer (Part E) Melanoma (Part E) Squamous Cell Cancer of the Head and Neck (Part E) Triple Negative Breast Cancer (Part F) Adrenocortical Carcinoma (Part G) Mesothelioma (Part G) High-circulating Myeloid-derived Suppressor Cells (Part H) Collapse <<	Phase 1	Recruiting	September 2019	United States, California ... more >> UCSD Recruiting San Diego, California, United States, 92093 UCLA Recruiting Santa Monica, California, United States, 90404 United States, Florida Hematology Oncology Associates of the Treasure Coast Recruiting Port Saint Lucie, Florida, United States, 34952 United States, Georgia Emory University Recruiting Atlanta, Georgia, United States, 30322 United States, Massachusetts Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, 02116 Beth Israel Deaconess Medical Center Recruiting Boston, Massachusetts, United States, 02215 Dana-Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02215 United States, New Jersey Hackensack University Medical Center Recruiting Hackensack, New Jersey, United States, 07601 United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 United States, Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 South Texas Accelerated Research and Treatment (START) Recruiting San Antonio, Texas, United States, 78229 Collapse <<

• 参考文献

• [1] Evans CA, Liu T, et al. Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate. ACS Med Chem Lett. 2016 Jul 22;7(9):862-7.

  [2] Kaneda MM, Messer KS, et al. PI3Kγ is a molecular switch that controls immune suppression. Nature. 2016 Nov 17;539(7629):437-442.

  [3] De Vera AA, Gupta P, et al. Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo. Cancer Lett. 2019 Feb 1;442:91-103.