生物活性

• 靶点	BTK IC50:3nM

• 描述Acalabrutinib is a potent and selective Bruton's Tyrosine Kinase (BTK) inhibitor with IC50 of 3.0 nM^[3], it can bind covalently to C481 in the ATP pocket of BTK irreversibly and then inhibit the BCR signal pathway without effect on EGFR, ITK or TEC signaling^[4]. Acalabrutinib could decrease the surface expression of CD86 and CD69 in ex vivo at the doses of 0.34 - 1.8 mg/kg and 0.16 - 1.3 mg/kg respectively. Acalabrutinib also showed other related immune regulation including decreases NK cytolytic function, IFNgamma production and Th cell development^[3]. Other study shows that, acalabrutinib inhibits platelet aggregation by plaque with IC50 values of 0.34 ± 0.19 µM through targeting GPIb and GPVI signaling, thus block atherosclerotic plaque-triggered thrombus formation and retaining hemostasis of platelets^[5]. In vivo, treatment with acalabrutinib orally at a dose of 12.5 mg/kg twice daily (BID) resulted in tumor growth inhibition in models of diffuse large B cell lymphoma (OCI-LY10) and mantle cell lymphoma (Jeko-1). In OCI-LY10 xenograft model, tumor growth was significantly reduced by acalabrutinib for 28 days^[3]. Acalabrutinib has improved pharmacologic features, including favorable plasma exposure, rapid oral absorption, a short half-life, and the absence of irreversible targeting to alternative kinases. The only clinical study of rheumatoid arthritis commerced in April 2015 and in a 4 weeks study in 70 patients stable on methotrexate^[6]. What's more, acalabrutinib was granted accelerated approval by FDA for patients with relapsed or refractory mantle cell lymphoma who have received at least one previous therapy.
• 作用机制Acalabrutinib is a Bruton’s Tyrosine Kinase (BTK) inhibitor which forms a covalent bond with cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity, and acalabrutinib appears to have fewer effects than ibrutinib on platelets in aggregometry assays^[3].

• 动物研究
  剂量	Mice[3] (p.o.): min = 0.1 mg/kg, max = 30 mg/kg Dogs[4] (p.o.): min = 2.5 mg/kg, max = 20 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
  NCT03740529	Chronic Lymphocytic Leukemia ... more >> Waldenstrom's Macroglobulinemia Mantle Cell Lymphoma Marginal Zone Lymphoma B-cell Lymphoma Small Lymphocytic Lymphoma Collapse <<	Phase 1 Phase 2	Recruiting	April 2021	United States, Tennessee ... more >> Sarah Cannon Research Institute at Tennessee Oncology Recruiting Nashville, Tennessee, United States, 37203 Contact: Ian W Flinn, MD, PhD Collapse <<
  NCT02570711	Metastatic Pancreatic Cancer	Phase 2	Terminated(Sponsor Decision)	-	United States, Texas ... more >> International Cancer Center Houston, Texas, United States, 77030 MD Anderson Houston, Texas, United States Collapse <<
  NCT03685708	Hepatitis Saf... more >>ety and Tolerability Collapse <<	Phase 2	Recruiting	May 15, 2020	United States, Maryland ... more >> National Institutes of Health Clinical Center Recruiting Bethesda, Maryland, United States, 20892 Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov Collapse <<

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