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 Citrate is the citrate form of Ixazomib. 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.
• 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
  NCT03590652	Relapsed/Refractory Multiple M... more >>yeloma Collapse <<	Phase 2	Recruiting	October 1, 2021	United States, California ... more >> UCSD Moores Cancer Center Recruiting La Jolla, California, United States, 92093 Contact: Caitlin Costello, MD    858-822-6600    ccostello@ucsd.edu    Contact: Jesika Reiner       jreiner@ucsd.edu Collapse <<
  NCT00893464	Lymphoma	Phase 1	Completed	-	United States, California ... more >> Tower Cancer Research Center Beverly Hills, California, United States, 90211 United States, Colorado Rocky Mountain Cancer Center Denver, Colorado, United States, 80218 United States, Kansas Kansas University Medical Center Westwood, Kansas, United States, 66160 United States, New York Cornell University New York City, New York, United States, 10021 United States, Pennsylvania Thomas Jefferson University Philadelphia, Pennsylvania, United States, 19107 United States, Wisconsin University of Wisconsin Madison Madison, Wisconsin, United States, 53792 Canada, Quebec Jewish General Hospital Montreal, Quebec, Canada, H3T 1E2 Collapse <<
  NCT03236792	AL Amyloidosis	Phase 1 Phase 2	Recruiting	June 2020	United States, New York ... more >> Icahn School of Medicine at Mount Sinai Recruiting New York, New York, United States, 10029 Contact: Keren Osman, MD          Contact: Sonia Rai, MHA,MD    212-241-6021    sonia.rai@mssm.edu    Principal Investigator: Keren Osman, MD          Columbia University Medical Center Not yet recruiting New York, New York, United States, 10032 Contact: Suzanne Lentzsch, MD,PhD          Memorial Sloan Kettering Cancer Center Not yet recruiting New York, New York, United States, 10065 Contact: Heather Landau, MD          Contact: Beth Hoover       HooverE@mskcc.org    Principal Investigator: Heather Landau, MD Collapse <<

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• 参考文献

• [1] Chauhan D, Tian Z, et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res. 2011 Aug 15;17(16):5311-21.

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