生物活性

• 靶点	BTK IC50:0.5nM

• 描述Btk (Bruton tyrosine kinase), a non-receptor tyrosine kinase, is specifically required for BCR signaling which contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. Ibrutinib, also called as PCI-32765 or imbruvica, is a potent Btk inhibitor with IC50 of 0.5 nM (measured by 33P filtration binding assay), modestly potent to Blk (IC₅₀= 0.5 nM), Bmx (IC₅₀= 0.8 nM), CSK (IC₅₀= 2.3 nM), FGR (IC₅₀= 2.3 nM), BRK (IC₅₀= 3.3 nM), HCK (IC₅₀= 3.7 nM), less potent to EGFR (IC₅₀= 5.6 nM), Yes (IC₅₀= 6.5 nM), ErbB2 (IC₅₀= 9.4 nM), ITK (IC₅₀= 10.7 nM). Ibrutinib can selectively inhibit B-cell signaling and activation, including inhibition of autophosphorylation of Btk, phosphorylation of Btk's physiological substrate PLCγ and phosphorylation of a further downstream kinase ERK, in DOHH2 cells. Continuous exposure to 10 nM Ibrutinib for 18h completely prevented up-regulation of CD69, the B-cell activation marker. In vivo study shows that Btk inhibition by Ibrutinib is efficacious for autoimmune disease animal model. Oral treatment daily for 11 days with 12.5 mg/kg of Ibrutinib can inhibit collagen-induced arthritis in mice^[1]. Up to now, Ibrutinib is approved to the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft versus host disease^[2].
• 作用机制Ibrutinib can bind covalently to a cysteine residue (Cys-481) in the active site, leading to potent and irreversible inhibition of Btk enzymatic activity^[3]. Notice: BMX, EGFR, ErbB2, ITK, JAK3,AK3 and TEC is the kinase that contains a cysteine residue aligning with Cys-481 same as Btk, resulting in the binding with Ibrutinib^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human DOHH2 cells	-	Cytotoxic assay	72 h	Cytotoxicity against human DOHH2 cells assessed as growth inhibition after 72 hrs by CellTiter-Glo luminescent cell viability assay, IC50=0.41 μM.	24915291
  human Pfeiffer cells	-	Function assay	72 h	Cytotoxicity against human Pfeiffer cells assessed as growth inhibition after 72 hrs by CellTiter-Glo luminescent cell viability assay, IC50=2 nM.	24915291
  human Ramos cells	-	Function assay	1 h	Inhibition of Btk in human Ramos cells assessed as inhibition of PLC-gamma2 phosphorylation at Tyr1217 after 1 hr by Western blot analysis, IC50=14 nM.	24915291

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• 动物研究
  剂量	Mice[3]: min = 2.5 mg/kg, max = 25 mg/kg
  给药途径	p.o.

• 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
  NCT02824029	Classical Hodgkin Lymphoma ... more >> Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma Collapse <<	Phase 2	Recruiting	February 2019	United States, Michigan ... more >> Wayne State University/Karmanos Cancer Institute Recruiting Detroit, Michigan, United States, 48201 Contact: Radhakrishnan Ramchandren    313-576-8739       Principal Investigator: Radhakrishnan Ramchandren, M.D.          Sub-Investigator: Divaya Bhutani, M.D.          Sub-Investigator: Jay Yang, M.D.          Sub-Investigator: Jeffrey Zonder, M.D.          Sub-Investigator: Charles Schiffer, M.D.          Sub-Investigator: Abhinav Deol, M.D.          United States, Texas M D Anderson Cancer Center Not yet recruiting Houston, Texas, United States, 77030 Contact: Michelle A. Fanale    713-792-2860    mfanale@mdanderson.org    Principal Investigator: Michelle A. Fanale Collapse <<
  NCT03021460	Metastatic Melanoma ... more >> Stage III Skin Melanoma Stage IIIA Skin Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Collapse <<	Phase 2	Recruiting	February 1, 2021	United States, Minnesota ... more >> Mayo Clinic Recruiting Rochester, Minnesota, United States, 55905 Contact: Clinical Trials Referral Office    855-776-0015       Principal Investigator: Matthew S. Block Collapse <<
  NCT02899078	Metastatic Renal Cell Cancer ... more >> Stage IV Renal Cell Cancer Collapse <<	Phase 1 Phase 2	Recruiting	May 2020	United States, California ... more >> University of California Davis Comprehensive Cancer Center Recruiting Sacramento, California, United States, 95817 Contact: Primo N. Lara, M.D.    916-734-3771    pnlara@ucdavis.edu    Principal Investigator: Primo N. Lara, M.D.          Sub-Investigator: Chong-Xian Pan, M.D., Ph.D. Collapse <<

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• 参考文献

• [1] Honigberg LA, Smith AM, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80.

  [2] Pan Z, Scheerens H, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2007 Jan;2(1):58-61.