生物活性

• 描述Cereblon (CRBN) is a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, that promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Alolos and Ikaros. CC-122 is a new chemical entity termed pleiotropic pathway modifier, binds CRBN and induces apoptosis in a broad panel of diffuse large B-cell lymphoma (DLBCL), and stimulated IL-2 production in primary T cells. In vitro, CC-122 induced growth arrest and apoptosis in activated B-cell and germinal center B-cell DLBCL cell lines at concentration ranging in 0.1 – 10 μM. Treatment with 10 μM CC-122 promoted CRBN-Ikaros interaction and subsequent proteasomal degradation of Aiolos and Ikaros in DLBCL cell lines TMD8, OCI-LY10 and Karpase 422^[3]. Treatment with 1 μM CC-122 inhibited cell invasion and migration in hepatocellular carcinoma (HCC) cell lines. In addition, CC-122 significantly reduced TCG-4 J and its target genes SPP1, AXIN2, MMP7, ASPH, CD24, ANXA1, and CAMK2N1^[4]. In vivo, treatment with 30 mg/kg once daily for 30 days significantly decreased tumor growth in OCILY10 ABC-DLBCL and WSU-DLCL2 derived xenograft models. Administration of CC-122 at 30 mg/kg once daily for 24h significantly decreased Aiols and IKaros expression in WSU-DLCL2 xenograft transplanted mice^[3]. Oral administration of CC-122 at 30 mg/kg for 40 days reduced growth rate of HAK-1A-J tumors in HCC xenografts model^[4]. A phase I Clinical trial study shows that CC-122 might regulate the NK phenotype and its activity due to the reduced accumulation of myeloid derived suppressor cell and eventually decrease the Tregs subsets^[5].
• 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
  NCT03310619	Lymphoma, Non-Hodgkin ... more >> Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular Collapse <<	Phase 1 Phase 2	Recruiting	March 4, 2022	United States, California ... more >> City of Hope National Medical Center Recruiting Duarte, California, United States, 91010 United States, Illinois Northwestern University School of Medicine Recruiting Chicago, Illinois, United States, 60611-5975 United States, Massachusetts Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, 02114 United States, Nebraska University of Nebraska Medical Center Recruiting Omaha, Nebraska, United States, 68198-7680 United States, Pennsylvania University of Pennsylvania Recruiting Philadelphia, Pennsylvania, United States, 19104 United States, Texas The University of Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Collapse <<
  NCT03340662	Healthy Volunteer	Phase 1	Completed	-	United States, Texas ... more >> PPD Phase 1 Clinic Austin, Texas, United States, 78744 Collapse <<
  NCT02031419	Lymphoma, Large B-Cell, Diffus... more >>e Collapse <<	Phase 1	Active, not recruiting	November 30, 2020	United States, California ... more >> Sansum Clinic Santa Barbara, California, United States, 93105 Stanford Cancer Center Stanford, California, United States, 94305 United States, Colorado Rocky Mountain Cancer Centers, LLP [Boulder-COBO] Boulder, Colorado, United States, 80303 United States, Connecticut Yale Cancer Center New Haven, Connecticut, United States, 06510 United States, Florida H. Lee Moffitt Cancer Cencer and Research Institute Tampa, Florida, United States, 33612 United States, Illinois Northwestern University, Division of Hematology Oncology, Dept. of Medicine Chicago, Illinois, United States, 60611 Illinois Cancer Specialists Niles, Illinois, United States, 60714 United States, Minnesota Mayo Clinic Rochester, Minnesota, United States, 55905 United States, Oregon Willamette Valley Cancer Center Eugene, Oregon, United States, 97401-8122 United States, Tennessee West Cancer Center Germantown, Tennessee, United States, 38138 Sarah Cannon Cancer Center Nashville, Tennessee, United States, 37203 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030-400 United States, Wisconsin University of Wisconsin Osteoporosis Clinical Center and Research Program Madison, Wisconsin, United States, 53792 Canada, Alberta Cross Cancer Institute Edmonton, Alberta, Canada, T6G 1Z2 Canada, Ontario Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 France Institut Bergonie Centre Regional de Lutte Contre Le Cancer de Bordeaux Et Sud Ouest Bordeaux, France, 33076 Centre Leon Berard Lyon, France, 69373 Institut Gustave Roussy Villejuif Cedex, France, 94805 Italy Istituto Nazionale Dei Tumori Milano, Italy, 20133 Istituto Clinico Humanitas Rozzano (MI), Italy, 20089 Azienda Sanitaria Ospedaliera San Giovanni Battista Molinette Turin, Italy, 10126 Collapse <<

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• 参考文献

• [1] Hagner PR, Man HW, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. 2015 Aug 6;126(6):779-89.

  [2] Jacques V, Czarnik AW, et al. Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):E1471-9.

  [3] Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, Bjorklund C, Havens CG, Lu G, Rychak E, Raymon H, Narla RK, Barnes L, Khambatta G, Chiu H, Kosek J, Kang J, Amantangelo MD, Waldman M, Lopez-Girona A, Cai T, Pourdehnad M, Trotter M, Daniel TO, Schafer PH, Klippel A, Thakurta A, Chopra R, Gandhi AK. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. 2015 Aug 6;126(6):779-89.

  [4] Tomimaru Y, Aihara A, Wands JR, Aloman C, Kim M. A Novel Drug, CC-122, Inhibits Tumor Growth in Hepatocellular Carcinoma through Downregulation of an Oncogenic TCF-4 Isoform. Transl Oncol. 2019 Oct;12(10):1345-1356.

  [5] Cubillos-Zapata C, Cordoba R, Avendaño-Ortiz J, Arribas-Jiménez C, Hernández-Jiménez E, Toledano V, Villaescusa T, Moreno V, López-Collazo E. CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma. Oncoimmunology. 2016 Sep 16;5(12):e1231290.

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