生物活性

• 描述The proteasome is a multicatalytic protease complex consisted of a 20S proteolytic core and two 19S regulatory caps that assemble with the core at either end to form a 26S complex. The proteasome is responsible for the ubiquitin-dependent turnover of cellular proteins and regulates cell proliferation and survival pathways. Oprozomib is a tripeptide proteasome inhibitor that selectively inhibits chymotrypsin-like activity of both the constitutive proteasome (β5) and immunoproteasome (LMP7) with IC50 values of 36nM and 82nM, respectively. In vitro, oprozomib inhibited cell viability of a pair of uterine sarcoma tumor cell lines MES(MDR-) and MES(MDR+) with IC50 values of 25nM and 1322nM, respectively^[2]. Oprozomib inhibited the growth of UMSCC-1, CALL33, carfilzomib-resistant UMSCC-1 and carfilzomib-resistant CAL33 cell lines with IC50 values of 88.2nM, 59.3nM, 2294nM and 1112nM, respectively^[3]. In addition, oprozomib inhibited the breast cancer cell lines MDA-MB-231 and BT-549 with IC50 values of 0.079μM and 0.05μM, respectively. Oprozomib also increased doxorubicin-induced cytotoxic effects and apoptosis by enhancing doxorubicin-induced JNK/p38/ MAPK phosphorylation in the breast cancer cell lines MDA-MB-231 and BT-549^[4]. In vivo, oral administration of oprozomib at 30mg/kg resulted in more than 80% proteasome inhibition in blood, liver and adrenal gland, and elicited an antitumor response equivalent to intravenously administered carfilzomib in RL cells and CT26 cells mouse xenograft models^[2].
• 作用机制Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome.^[2].
• 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
  NCT02939183	Relapsed or Refractory Multipl... more >>e Myeloma Collapse <<	Phase 1	Recruiting	April 29, 2020	United States, California ... more >> Research Site Recruiting West Hollywood, California, United States, 90069 United States, Florida Research Site Recruiting Tampa, Florida, United States, 33612 United States, Georgia Research Site Recruiting Atlanta, Georgia, United States, 30322 United States, Illinois Research Site Recruiting Chicago, Illinois, United States, 60637-6613 United States, Maryland Research Site Recruiting Bethesda, Maryland, United States, 20817 United States, Missouri Research Site Recruiting Saint Louis, Missouri, United States, 63110 United States, New York Research Site Recruiting New York, New York, United States, 10021 United States, North Carolina Research Site Recruiting Charlotte, North Carolina, United States, 28204 United States, Wisconsin Research Site Recruiting Milwaukee, Wisconsin, United States, 53226 Australia, Victoria Research Site Recruiting Clayton, Victoria, Australia, 3168 Australia, Western Australia Research Site Recruiting Murdoch, Western Australia, Australia, 6150 Research Site Recruiting Nedlands, Western Australia, Australia, 6009 Belgium Research Site Recruiting Gent, Belgium, 9000 Canada, Alberta Research Site Recruiting Calgary, Alberta, Canada, T2N 2T9 Canada, Ontario Research Site Recruiting Toronto, Ontario, Canada, M5G 2C1 Netherlands Research Site Recruiting Rotterdam, Netherlands, 3015 CE Spain Research Site Recruiting Salamanca, Castilla León, Spain, 37007 Research Site Recruiting Pamplona, Navarra, Spain, 31008 Collapse <<
  NCT02244112	Advanced Non-Central Nervous S... more >>ystem (CNS) Malignancies Collapse <<	Phase 1	Active, not recruiting	February 28, 2019	United States, Colorado ... more >> University of Colorado Anschutz Medical Campus Aurora, Colorado, United States United States, Georgia Winship Cancer Institute Atlanta, Georgia, United States United States, Michigan Henry Ford Hospital Detroit, Michigan, United States United States, Texas Mary Crowley Cancer Research Centers - Medical City Dallas, Texas, United States University of Texas MD Anderson Cancer Center Houston, Texas, United States South Texas Accelerated Research Therapeutics, LLC San Antonio, Texas, United States United States, Utah Huntsman Cancer Institute Salt Lake City, Utah, United States Collapse <<
  NCT02072863	Multiple Myeloma	Phase 1 Phase 2	Completed	-	Greece ... more >> Department of Clinical Therapeutics, University of Athens Athens, Attica, Greece Italy Ospedale Oncologico Regionale Rionero in Vulture, Potenza, Italy Azienda Ospedaliera Universitaria S Martino Genova, Italy AOU Maggiore della Carita, SCDU Heamatology Novara, Italy University of Rome Rome, Italy Hospital City of Health and Science of Turin, Hematology 1 Division Turin, Italy Netherlands Vrijc Universiteit Medisch Centrum, Department of Hematology Amsterdam, Netherlands Erasmus MC, Department of Hematology Rotterdam, Netherlands Collapse <<

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• 参考文献

• [1] Chauhan D, Singh AV, et al. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood. 2010 Dec 2;116(23):4906-15.

  [2] Zhou H, Aujay M, Bennett M K, et al. Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). Journal of Medicinal Chemistry, 2009, 52(9): 3028-3038

  [3] Zang Y, Kirk C J, Johnson D E, et al. Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Cancer Biology & Therapy, 2014, 15(9): 1142-1152

  [4] Shi Y, Bieerkehazhi S, Ma H, et al. Next-generation proteasome inhibitor oprozomib enhances sensitivity to doxorubicin in triple-negative breast cancer cells. International Journal of Clinical and Experimental Pathology, 2018, 11(5): 2347-2355