生物活性

• 描述The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. Proteasome Subunit β5 is a component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. Proteasome Subunit β5 displays a chymotrypsin-like activity. Carfilzomib is a proteasome inhibitor, specifically inhibiting the chymotrypsin-like (ChT-L) activity at the β5 subunits of the core 20S proteasome^[3]. According to a report, extracts from multiple myeloma ANBL-6 cells were exposed to increasing concentrations of carfilzomib and assayed for 20S catalytic activities. Carfilzomib displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, with over 80% inhibition at the dose of 10 nM and little or no effect on the PGPH and T-L activities at doses up to 100 nM. In an ELISA assay utilizing cell extracts from ANBL-6 cells, designed to identify subunit binding, short exposure to Carfilzomib at the concentration as low as 0.1 μM exhibited preferential binding specificity for the β5 constitutive 20S proteasome. Based on a WST-1 assay, the inhibitory IC50s of Carfilzomib against multiple myeloma ANBL-6 and RPMI8226 cells were both less than 5 nM, with the drug incubation time of 24h. In a caspase activity assay, ANBL-6 cells were exposed to a 1-hour pulse of 100 nM Carfilzomib and allowed to recover for 8 hours. The results indicated that Carfilzomib increased caspase-3 activity approximately 6-fold, and caspase-8, caspase-9 activity approximately 4-fold^[4]. In a mouse model of bone marrow disseminated multiple myeloma established by intravenous injection of 5TGM1-GFP cells into KaLwRij mice, Carfilzomib was intravenously administrated at the dose of 3 mg/kg daily for 2 days. The treatment of Carfilzomib significantly decreased tumor burden as measured by serum levels of the clonotypic antibody IgG2b and by percentage of bone marrow or spleen GFP-expressing tumor cells. Protection from tumor-induced bone loss was also observed by microCT^[5].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  1483	200 nM	Apoptosis Asssay	24 h	induce the cell apoptosis co-treatment with ONX 0912	22929803
  1483	-	Growth Inhibition Assay	-	IC50=50.5 ± 11.9 nM	22929803
  Cal33	-	Growth Inhibition Assay	-	IC50=49.3 ± 8.9 nM	22929803

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• 动物研究
  剂量	Mice: 2 mg/kg[3] (i.v.), 5 mg/kg - 10 mg/kg[4] (i.v.)
  给药途径	i.v.

• 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
  NCT01962792	Multiple Myeloma	Phase 1 Phase 2	Active, not recruiting	April 2019	United States, California ... more >> City of Hope Duarte, California, United States, 91010 University of California Los Angeles Los Angeles, California, United States, 90095 United States, Colorado Colorado Blood Cancer Institute Denver, Colorado, United States, 80218 United States, Nebraska University of Nebraska Medical Center Omaha, Nebraska, United States, 68198 United States, New York New York Presbyterian Hospital - Weill-Cornell New York, New York, United States, 10021 Mount Sinai Hospital New York, New York, United States, 10029 United States, North Carolina Carolinas Healthcare System Charlotte, North Carolina, United States, 28204 Duke University Medical Center Durham, North Carolina, United States, 27705 United States, Ohio University of Cincinnati Cincinnati, Ohio, United States, 45267 Cleveland Clinic Cleveland, Ohio, United States, 44195 United States, Pennsylvania Thomas Jefferson University Philadelphia, Pennsylvania, United States, 19107 United States, South Carolina MUSC Hollings Cancer Center Charleston, South Carolina, United States, 29425 United States, Tennessee Vanderbilt Ingram Cancer Center Nashville, Tennessee, United States, 37232 United States, Texas University of Texas Southwestern Medical Center Dallas, Texas, United States, 75390 Methodist Healthcare System San Antonio, Texas, United States, 78229 United States, Virginia Virginia Commonwealth University Richmond, Virginia, United States, 23298 Canada, Quebec McGill University Montreal, Quebec, Canada, QC H4A 3J1 Collapse <<
  NCT02756663	Multiple Myeloma	Phase 2	Withdrawn	February 2021	-
  NCT02294357	Multiple Myeloma	Phase 2	Recruiting	December 2018	United States, California ... more >> California Cancer Associates for Research & Excellence (cCARE) Recruiting Encinitas, California, United States, 92024 Contact: Alberto Bessudo, MD          Contact: Beth Kimball, RN    (760) 452-3909    BKimball@ccare.com    Wellness Oncology and Hematology Recruiting West Hills, California, United States, 91307 Contact: Ashkan Lashkari, MD          Contact: Mary Mau    (818) 346-1773    mary@wellnessoncology.com    James R Berenson, MD, Inc. Recruiting West Hollywood, California, United States, 90069 Contact: James Berenson, MD          Contact: Regina Swift, RN, BSN    310-623-1222    rswift@berensononcology.com    United States, Florida Cancer Specialists of North Florida Recruiting Fleming Island, Florida, United States, 32003 Contact: Mehdi Moezi, MD          Contact: Jenni Bachhofer    (904) 363-7462    Jenni.Bachhofer@CSNF.us    United States, New York Hudson Valley Hem/Onc Associates Completed Poughkeepsie, New York, United States, 12601 United States, Ohio Gabrail Cancer Center Recruiting Canton, Ohio, United States, 44718 Contact: Nashat Gabrail, MD          Contact: Kirstie Armstrong    (330) 492-3345    karmstrong@gabrailcancercenter.com    United States, Texas Blood & Cancer Center of East Texas Completed Tyler, Texas, United States, 75701 Collapse <<

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