生物活性

• 描述The ubiquitin-proteasome system is responsible for the regulation of cellular protein homeostasis. By inhibiting proteasome activity, the anti-proliferative signals and the apoptotic pathways can be activated in cells, which makes proteasome an attractive therapeutic target in cancer treatment. Ixazomib is an N-capped dipeptidyl leucine boronic acid that inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nmol/l (Ki value of 0.93 nmol/l). It also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites with IC50 values of 31 and 3500 nmol/l, respectively. The proteasome dissociation half-life (t_1/2) for ixazomib is 18 minutes. In MDA-MB-231 cells expressing a 4  Ub-Luc reporter, ixazomib inhibited proteasome activity with an EC50 value of 525 nmol/l. In HEK293 cells stably expressing a NF-κB-Luc reporter, ixazomib inhibited TNF-α-induced activation of NF-κB pathway with an EC50 value of 55 nmol/l. The anti-proliferative effects of ixazomib in A375 (lung), H460 (lung), HCT-116 (colon), and HT-29 (colon) cells were determined by cell viability assay with LD50 values ranged from 19 – 58 nmol/l. In mice i.v. administrated with a single dose of ixazomib at 14 mg/kg, the blood volume distribution at steady state was 20.2 L/kg. In Sprague-Dawley rats i.v. injected with a single of ixazomib at 0.2 or 0.3 mg/kg, the plasma exposure (AUC_0-48h) of ixazomib was 704 and 1070 h.ng/ml, respectively. In CB17-SCID mice bearing xenograft tumors, the maximum level of blood proteasome inhibition was 83.1% following an acute i.v. treatment of 14 mg/kg ixazomib. The tumor to blood AUE ratio for ixazomib in human prostate tumor (CWR22) and human lymphoma tumor (WSU-DLCL2s) xenografts was 1.56 and 2.03, respectively. Ixazomib dosed at 7 mg/kg or 14 mg/kg showed significant antitumor effects in xenografts 22 days after the administration.
• 作用机制Ixazomib inhibits 20S proteasome by binding to the chymotrypsin-like proteolytic (β5) site of the proteasome.

• 动物研究
  剂量	Mice: 2 mg/kg - 14 mg/kg[2] (i.v.), 3.5 mg/kg[3] (p.o>), 8 mg/kg[2] (p.o.), 11 mg/kg[1] (p.o.) Rat: 0.2 mg/kg, 0.3 mg/kg[1] (i.v.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Mice[4] Dose 14 mg/kg (i.v.) 11 mg/kg (p.o.) Administration i.v. p.o. F 59.5% (p.o.) Vd 20.2 L/kg (i.v.) Cmax 10500 ng/ml (i.v.) 1710 ng/ml (p.o.) AUC0→24h 9660 h·ng/ml (i.v.) 6310 h·ng/ml (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
  NCT02765854	Recurrent Plasma Cell Myeloma ... more >> Refractory Plasma Cell Myeloma Collapse <<	Phase 2	Recruiting	September 2020	United States, Georgia ... more >> Grady Memorial Hospital Recruiting Atlanta, Georgia, United States, 30303 Contact: Stephanie McMillan, RN, MSN    404-778-1361    sjmcmil@emory.edu    Emory University/Winship Cancer Institute Recruiting Atlanta, Georgia, United States, 30322 Contact: Jennifer Shipp    404-778-4191    jennifer.shipp@emory.edu    United States, Michigan University of Michigan/Rogel Cancer Center Recruiting Ann Arbor, Michigan, United States, 48109 Contact: Craig Cole, MD       colec@med.umich.edu    United States, Missouri Washington University/Siteman Cancer Center Recruiting Saint Louis, Missouri, United States, 63110 Contact: Ravi Vij, MD       rvij@wustl.edu Collapse <<
  NCT02400437	Waldenstrom's Macroglobulinemi... more >>a Collapse <<	Phase 2	Active, not recruiting	September 2021	United States, Massachusetts ... more >> Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 Collapse <<
  NCT02158975	Lymphoma, T-Cell	Phase 2	Completed	-	United States, Michigan ... more >> University of Michigan Hospital Ann Arbor, Michigan, United States, 48109 Collapse <<

• 更多
• 参考文献

• [1] Kupperman E, Lee EC, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70(5):1970-80.

  [2] Ghobadi A, Rettig MP, et al. Ixazomib, an oral proteasome inhibitor, induces rapid mobilization of hematopoietic progenitor cells in mice. Blood. 2018 Jun 7;131(23):2594-2596.

  [3] Liu W, Chen J, et al. Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma. Oncotarget. 2017 Aug 21;9(1):346-360.

  [4] MLN2238