Zanubrutinib (BGB-3111)
(Synonyms: 泽布替尼; BGB-3111) 目录号 : GC34075
A potent and covalent BTK inhibitor
Cas No.:1691249-45-2
Sample solution is provided at 25 µL, 10mM.
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Zanubrutinib is a potent and covalent inhibitor of Bruton's tyrosine kinase (BTK; IC50 = 0.3 nM).1 It is selective for BTK over a panel of 304 kinases at 1 μM but does inhibit EGFR, Tec, Blk, BMX, HER4, and TXK (IC50s = 0.62-33 nM). Zanubrutinib inhibits phosphorylation of BTK at Y233 (IC50 = 1.8 nM) in Ramos cells and reduces viability of REC-1 cells (IC50 = 0.36 nM). In vivo, zanubrutinib (2.5 and 7.5 mg/kg) reduces tumor volume in an OCI-LY10 diffuse large B cell lymphoma (DLBCL) mouse xenograft model.
1.Guo, Y., Liu, Y., Hu, N., et al.Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of bruton's tyrosine kinaseJ. Med. Chem.62(17)7923-7940(2019)
| Cas No. | 1691249-45-2 | SDF | |
| 别名 | 泽布替尼; BGB-3111 | ||
| Canonical SMILES | NC(C1=C2N(N=C1C3=CC=C(OC4=CC=CC=C4)C=C3)[C@H](C5CCN(C(C=C)=O)CC5)CCN2)=O | ||
| 分子式 | C27H29N5O3 | 分子量 | 471.55 |
| 溶解度 | DMSO : ≥ 56.75 mg/mL (120.35 mM);Ethanol : < 1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1207 mL | 10.6033 mL | 21.2067 mL |
| 5 mM | 0.4241 mL | 2.1207 mL | 4.2413 mL |
| 10 mM | 0.2121 mL | 1.0603 mL | 2.1207 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
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Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase
J Med Chem 2019 Sep 12;62(17):7923-7940.PMID:31381333DOI:10.1021/acs.jmedchem.9b00687.
Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton's Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia
Drug Des Devel Ther 2021 Mar 2;15:919-926.PMID:33688166DOI:10.2147/DDDT.S250823.
The understanding of the B cell receptor (BCR) pathway and its contribution to chronic lymphocytic leukemia (CLL) pathogenesis have led to the development of targeted BCR inhibitors which have transformed the treatment paradigm of CLL. Ibrutinib is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor which has demonstrated improvements in both progression free (PFS) and overall survival (OS) in both the treatment naïve and relapsed/refractory setting as compared to traditional chemoimmunotherapy. Despite its clinical efficacy, many patients discontinue treatment due to adverse events, which are thought to be mediated through off-target kinase inhibition. Zanubrutinib is a second-generation non-covalent BTK inhibitor with higher potency, allowing for inhibition of BTK with fewer off target effects. Early phase clinical trials have demonstrated excellent efficacy and a well-tolerated safety profile. Long-term follow-up is needed, but zanubrutinib holds promise to be an effective therapy for CLL with a manageable side effect profile and will be an exciting addition to our treatment paradigm.
A randomized phase 3 trial of Zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study
Blood 2020 Oct 29;136(18):2038-2050.PMID:32731259DOI:10.1182/blood.2020006844.
Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with Zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or Zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) Zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and Zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among Zanubrutinib recipients. Incidence of neutropenia was higher with Zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that Zanubrutinib and ibrutinib are highly effective in the treatment of WM, but Zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.
Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia
N Engl J Med 2023 Jan 26;388(4):319-332.PMID:36511784DOI:10.1056/NEJMoa2211582.
Background: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with Zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, Zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. Methods: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive Zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether Zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of Zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. Results: At a median follow-up of 29.6 months, Zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the Zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received Zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored Zanubrutinib. The percentage of patients with an overall response was higher in the Zanubrutinib group than in the ibrutinib group. The safety profile of Zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. Conclusions: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received Zanubrutinib than among those who received ibrutinib, and Zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).
Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects
Front Cell Dev Biol 2021 Mar 11;9:630942.PMID:33777941DOI:10.3389/fcell.2021.630942.
The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and Zanubrutinib, are approved both in the United States and in Europe, and Zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.