生物活性

• 靶点	BTK IC50:0.5nM

• 描述Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the B cell receptor (BCR) signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity^[3]. AVL-292 is a highly selective, covalent Btk inhibitor with IC₅₀ less than 0.5 nM. In Ramos cells which express an intact BCR signaling pathway, AVL-292 (0.1 nM-3 μM) potently inhibited Btk autophosphorylation on Tyr223 (EC₅₀ = 8 nM), phosphorylation of the Btk substrate, PLCγ2, as well as activation of the downstream kinase. In the collagen-induced arthritis (CIA) model of arthritis, AVL-292 (3-30 mg/kg, p.o.) dose-dependently suppressed the clinical signs of inflammatory disease including reduction in joint and paw swelling and visible redness of the affected paws. Reduction of clinical signs of disease was measured at 95%, 85% and 50% for 30, 10 and 3mg/kg treatment respectively^[3].

• 动物研究
  剂量	Mice: 50 mg/kg[3] (p.o.)
  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
  NCT01351935	B Cell Non-Hodgkin's Lymphoma ... more >> Chronic Lymphocytic Leukemia Waldenstrom Macroglobulinemia Collapse <<	Phase 1	Completed	-	United States, Alabama ... more >> Clearview Cancer Institute Oncology Specialties, P.C Huntsville, Alabama, United States, 35805 United States, Arizona University of Arizona (SPORE) Tucson, Arizona, United States, 85719 United States, California University of California San Diego LaJolla, California, United States, 92093-0960 United States, Florida Mayo Clinic Jacksonville Jacksonville, Florida, United States, 32224 United States, Illinois Northwestern University Chicago, Illinois, United States, 60611 United States, Indiana Horizon Oncology Center LaFayette, Indiana, United States, 47905 United States, Massachusetts Dana Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, New York Mount Sinai School of Medicine and Mount Sinai Graduate School of Biological Sciences New York, New York, United States, 10029 University of Rochester Medical Center Rochester, New York, United States, 14642 United States, Ohio Cleveland Clinic Cleveland, Ohio, United States, 44195 United States, Texas The University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 University of Texas Health Sciences Center San Antonio, Texas, United States, 78229 US Oncology The Woodlands, Texas, United States, 77380 Collapse <<
  NCT01692184	Healthy	Phase 1	Completed	-	United States, Texas ... more >> Covance Clinical Research Unit Dallas, Texas, United States, 75247 Collapse <<

• 参考文献

• [1] Eda H, Santo L, et al. A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity. Leukemia. 2014 Sep;28(9):1892-901.

  [2] Evans EK, Tester R, et al. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013 Aug;346(2):219-28.

  [3] Evans EK, Tester R, Aslanian S, Karp R, Sheets M, Labenski MT, Witowski SR, Lounsbury H, Chaturvedi P, Mazdiyasni H, Zhu Z, Nacht M, Freed MI, Petter RC, Dubrovskiy A, Singh J, Westlin WF. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013 Aug;346(2):219-28. doi: 10.1124/jpet.113.203489. Epub 2013 May 24. PMID: 23709115.