生物活性

• 描述Bcr-Abl is a constitutively active tyrosine kinase that drives survival and proliferation through multiple downstream pathways^[3]. DCC-2036 is a Bcr-Abl inhibitor for Abl1^WT, Abl1^T315I and Abl1^H396P with IC50 values of 0.8 nM, 4 nM and 1.4 nM, respectively^[1]. In vitro, DCC-2036 effectively inhibited proliferation of the Ba/F3 cells expressing Bcr-Abl1^WT with IC50 values of 5.4 nM, but DCC-2036 also retained potency against Ba/F3 cells expressing Bcr-Abl1 mutants that was resistant to imatinib, dasatinib, and nilotinib. DCC-2-35 also inhibited proliferation of the Ba/F3 cells expressing Bcr-Abl1^T315I and the Ph⁺ cell line K562 with IC50 values of 13 nM and 5.5 nM, respectively. In addition, DCC-2036 inhibited proliferation of several common TKI-resistant mutants of Bcr- Abl1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50 values ranging from 6 – 150 nM. DCC-2036 effectively inhibited autophosphorylation of Bcr-Abl1^WT and Bcr-Abl1^T315I with IC50 values of 29 nM and 18 nM, respectively, as well as the phosphorylation of STAT5 in Ba/F3 cells expressing Bcr-Abl1^WT or Bcr-Abl1^T315I with IC50 values of 28 nM and 13 nM, respectively. In vivo, a single oral dose of DCC-2036 at 100 mg/kg afforded circulating plasma levels that exceeded 12 μM for up to 24 hour, and effectively inhibited Bcr-Abl1 signaling for up to 8 hours in Ba/F3-Bcr-Abl1^T315I leukemia cells isolated from bone marrow and spleen of tumor-bearing mice, as assessed by intracellular flow cytometric staining for phospho-STAT5. Oral administration of DCC-2036 at 100 mg/kg twice daily significantly prolonged the survival of the mice bearing Ba/F3- Bcr-Abl1^T315I leukemia cells and reduced the leukemia cell burden in the spleens. Oral administration of DCC-2036 at doses of 60 - 100 mg/kg/d prolonged survival and reduced circulating leukemia cells in physiologically relevant mouse models of CML-like myeloproliferative neoplasia and Ph+ B-cell acute lymphoblastic leukemia induced by Bcr-Abl1^T315I[1].
• 作用机制DCC-2036 potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation^[1].
• 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
  NCT00827138	Chronic Myeloid Leukemia	Phase 1	Completed	-	United States, California ... more >> City of Hope Duarte, California, United States, 91010 United States, Florida H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida, United States, 33612 United States, Georgia Emory University Atlanta, Georgia, United States, 30322 United States, Illinois University of Chicago Chicago, Illinois, United States, 60637 United States, Kansas The University of Kansas Cancer Center Kansas City, Kansas, United States, 66160 United States, Maryland Sidney Kimmel Cancer Center at Johns Hopkins Baltimore, Maryland, United States, 21287 United States, Massachusetts Tufts Medical Center Boston, Massachusetts, United States, 02111 United States, Michigan University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan, United States, 48109 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 United States, Wisconsin Medical College of Wisconsin Milwaukee, Wisconsin, United States, 53226 Collapse <<
  NCT02824575	Breast Cancer ... more >> Breast Adenocarcinoma Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Recurrent Breast Carcinoma Stage IV Breast Cancer Collapse <<	Phase 1	Recruiting	July 2020	United States, New York ... more >> Montefiore Medical Center Recruiting Bronx, New York, United States, 10461 Contact: Karen Fehn, RN    718-405-8505    kfehn@montefiore.org    Contact: Vilma Calderon, BS    7184058505    vcaldero@montefiore.org Collapse <<
  NCT03601897	Locally Advanced or Metastatic... more >> Solid Tumor Collapse <<	Phase 1 Phase 2	Recruiting	July 1, 2020	United States, Alabama ... more >> University of Alabama Comprehensive Cancer Center Not yet recruiting Birmingham, Alabama, United States, 35233 United States, New York Montefiore Medical Center Not yet recruiting Bronx, New York, United States, 10467 United States, Oklahoma University of Oklahoma Health Sciences Center Recruiting Oklahoma City, Oklahoma, United States, 73104 United States, Pennsylvania Fox Chase Cancer Center Not yet recruiting Philadelphia, Pennsylvania, United States, 19111 United States, Tennessee Sarah Cannon Research Institute Recruiting Nashville, Tennessee, United States, 37203 United States, Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Collapse <<

• 更多
• 参考文献

• [1] Chan W W, Wise S C, Kaufman M, et al. Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036. Cancer Cell, 2011, 19(4): 556-568.

  [2] Eide CA, Adrian LT, et al. The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Res. 2011 May 1;71(9):3189-95.

  [3] Ohare T, Deininger M W, Eide C A, et al. Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia. Clinical Cancer Research, 2011, 17(2): 212-221.