生物活性

• 靶点

  JNK1 IC50:61nM

  JNK3 IC50:6nM

  JNK2 IC50:7nM

• 描述Aminopurine-based c-Jun N-terminal kinase (JNK) inhibitors have demonstrated pharmacological efficacy in animal models of inflammation and fibrosis. CC-930 is an orally active JNK inhibitor with IC50 values of 61±24, 7±2, and 6±2nM for JNK1, JNK2, and JNK3, respectively. It is kinetically competitive with ATP in JNK-dependent phosphorylation with K_i values of 44±3 and 6.2±0.6nM for JNK1 and JNK2, respectively. CC-930 blocked the formation of phosphorylated c-Jun in human peripheral blood mononuclear cells stimulated by phorbol-12-myristate-13-acetate and phytohemeagglutinin with an IC50 value of 1μM. It also inhibited p38α with an IC50 value of 3.4±1.1μM. The IC50 value of CC-930 in JNK cell lysate assay is 0.20±0.06μM. CC-930 inhibited epidermal growth factor receptor with an IC50 value of 0.38μM. In a mouse model of bleomycin-induced pulmonary fibrosis, treatment with CC-930 (25, 50, 100, and 150mg/kg) before and after (twice daily for 13 days) bleomycin stimulation significantly decreased the number of white blood cells, monocytes, and lymphocytes in bronchoalveolar lavage compared to the vehicle controls. The lung fibrosis score was also reduced by 18-32% in a dose-dependent manner after CC-930 tretament. In LPS-induced rats, oral administration of CC-930 inhibited the production of TNFα by 23% and 77% at a dosage of 10 and 30mg/kg, respectively{{Plantevin Krenitsky V, Nadolny L, Delgado M, et al. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett. 2012;22(3):1433- 1438. doi:10.1016/j.bmcl.2011.12.027|https://pubmed.ncbi.nlm.nih.gov/22244937/}}.
• 作用机制CC-930 inhibits JNK1 and JNK2 in an ATP-competitive manner^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  Jurkat T cells	-	Function assay	-	Inhibition of JNK-mediated GST tagged c-Jun phosphorylation in human Jurkat T cells compound treated for 30 mins prior anisomycin stimulation measured after 40 mins by fluorescence spectrophotometry, IC50=0.2 μM	22244937

• 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
  NCT01203943	Idiopathic Pulmonary Fibrosis ... more >> Pulmonary Fibrosis Fibrosis Interstitial Lung Disease Lung Diseases, Interstitial Collapse <<	Phase 2	Terminated(The benefit/ risk p... more >>rofile does not support continuation of this study.) Collapse <<	-	-
  NCT01466725	Discoid Lupus	Phase 2	Terminated(The benefit/risk pr... more >>ofile does not support continuation of this study.) Collapse <<	-	United States, Alabama ... more >> UAB Dermatology Birmingham, Alabama, United States, 35233 United States, California The Regents of the University of California Irvine, California, United States, 92697 United States, District of Columbia Medical Faculty Associates Washington, D.C., District of Columbia, United States, 20037 United States, Florida Advanced Pharma, CR, LLC Miami, Florida, United States, 33136 University of Miami - Department of Dermatology Miami, Florida, United States, 33136 United States, Illinois Rush Medical Center Chicago, Illinois, United States, 60612 North Shore University Health System Skokie, Illinois, United States, 60077 SIU School of Medicine Springfield, Illinois, United States, 62702 United States, Louisiana Tulane University School of Medicine New Orleans, Louisiana, United States, 70112 United States, Maryland John Hopkins University Baltimore, Maryland, United States, 21205 United States, Massachusetts Boston Cancer Center Boston, Massachusetts, United States, 02118 United States, Minnesota University of Minnesota-Department of Dermatology Minneapolis, Minnesota, United States, 55455 United States, New York University of Rochester Medical Center Rochester, New York, United States, 14623 United States, Ohio Ohio State Univ Medical Center, Division of Dermatology Columbus, Ohio, United States, 43221 United States, Rhode Island Rhode Island Hospital University Dermatology, Inc. Providence, Rhode Island, United States, 02903 United States, South Carolina Medical University of South Carolina Charleston, South Carolina, United States, 29425 United States, Texas Dermatology and Research Dallas, Texas, United States, 75230 University of Texas Dermatology Houston, Texas, United States, 77030 Sun Research Institute San Antonio, Texas, United States, 78215 Collapse <<

• 参考文献

• [1] Gan LT, Van Rooyen DM, et al. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent. J Hepatol. 2014 Dec;61(6):1376-84.

  [2] Plantevin Krenitsky V, Nadolny L, et al. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett. 2012 Feb 1;22(3):1433-8.

  [3] Plantevin Krenitsky V, Nadolny L, Delgado M, et al. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett. 2012;22(3):1433-1438. doi:10.1016/j.bmcl.2011.12.027