ACP-5862
(Synonyms: 阿可替尼代谢物27) 目录号 : GC39541
ACP-5862 是 Acalabrutinib 的主要活性的，循环的，吡咯烷开环代谢产物，对于 Bruton 酪氨酸激酶 (BTK) 的 IC50 为 5.0 nM。Acalabrutinib 是一种口服有效的，选择性的 BTK 抑制剂，IC50 和 EC50 分别为 3 nM 和 8 nM。
Cas No.:2230757-47-6
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ACP-5862 is a major active, circulating, pyrrolidine ring-opened metabolite of Acalabrutinib with an IC50 of 5.0 nM for Bruton tyrosine kinase (BTK)[1]. Acalabrutinib is an orally active, irreversible, and highly selective BTK inhibitor, with an IC50 of 3 nM and EC50 of 8 nM[2].
[1]. Podoll T, et al. Bioavailability, Biotransformation, and Excretion of the Covalent Bruton Tyrosine Kinase Inhibitor Acalabrutinib in Rats, Dogs, and Humans. Drug Metab Dispos. 2019 Feb;47(2):145-154. [2]. Herman SE, et al. The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2016 Nov 30
| Cas No. | 2230757-47-6 | SDF | |
| 别名 | 阿可替尼代谢物27 | ||
| Canonical SMILES | O=C(NC1=NC=CC=C1)C2=CC=C(C3=C4C(N)=NC=CN4C(C(CCCNC(C#CC)=O)=O)=N3)C=C2 | ||
| 分子式 | C26H23N7O3 | 分子量 | 481.51 |
| 溶解度 | DMSO: 250 mg/mL (519.20 mM) | 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.0768 mL | 10.384 mL | 20.768 mL |
| 5 mM | 0.4154 mL | 2.0768 mL | 4.1536 mL |
| 10 mM | 0.2077 mL | 1.0384 mL | 2.0768 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
ACP-5862 suppresses esophageal squamous cell carcinoma growth through inducing apoptosis via activation of endoplasmic reticulum stress and ROS production
Biochem Biophys Res Commun 2021 Jan 1;534:995-1002.PMID:33168189DOI:10.1016/j.bbrc.2020.10.052.
Esophageal squamous cell carcinoma (ESCC) is a common type of human oral malignancy with poor survival. Presently, it is necessary to find new and effective drugs for clinical therapy. This study aimed to identify the potential anti-tumor effects of ACP-5862, a major metabolite of acalabrutinib, on human ESCC progression, and to reveal the underlying mechanisms. Our findings suggested that ACP-5862 treatments markedly reduced the cell proliferation of ESCC cell lines in a time- and dose-dependent manner, while had no significant cytotoxicity to normal cells. Cell cycle arrest in G2/M phase was markedly induced by ACP-5862 in ESCC cells. Furthermore, apoptosis and endoplasmic reticulum (ER) stress were detected in ESCC cells treated with ACP-5862. Intriguingly, ACP-5862-induced apoptotic cell death was partly dependent on ER stress. Moreover, reactive oxygen species (ROS) was greatly triggered in ACP-5862-incubated ESCC cells, which was closely involved in apoptosis and ER stress mediated by ACP-5862. In addition, we showed that the expression of nuclear factor-erythroid 2-related factor-2 (Nrf-2) was considerably reduced in ACP-5862-treated cells. Importantly, ACP-5862 combined with Nrf-2 knockdown could further induce apoptosis and ER stress in ESCC cells compared with the ACP-5862 single group. Animal studies confirmed that repressing Nrf-2 promoted the anti-tumor effect of ACP-5862 on ESCC growth. Taken together, these findings demonstrated that ACP-5862 exerted anti-cancer effects on ESCC through inducing ER stress-mediated apoptosis via the ROS production. Meanwhile, ACP-5862 co-treated with Nrf-2 inhibitors may supply new and effective therapeutic strategies for ESCC treatment in future.
Identification and Characterization of ACP-5862, the Major Circulating Active Metabolite of Acalabrutinib: Both Are Potent and Selective Covalent Bruton Tyrosine Kinase Inhibitors
J Pharmacol Exp Ther 2023 Jan;384(1):173-186.PMID:36310034DOI:10.1124/jpet.122.001116.
Acalabrutinib is a covalent Bruton tyrosine kinase (BTK) inhibitor approved for relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. A major metabolite of acalabrutinib (M27, ACP-5862) was observed in human plasma circulation. Subsequently, the metabolite was purified from an in vitro biosynthetic reaction and shown by nuclear magnetic resonance spectroscopy to be a pyrrolidine ring-opened ketone/amide. Synthesis confirmed its structure, and covalent inhibition of wild-type BTK was observed in a biochemical kinase assay. A twofold lower potency than acalabrutinib was observed but with similar high kinase selectivity. Like acalabrutinib, ACP-5862 was the most selective toward BTK relative to ibrutinib and zanubrutinib. Because of the potency, ACP-5862 covalent binding properties, and potential contribution to clinical efficacy of acalabrutinib, factors influencing acalabrutinib clearance and ACP-5862 formation and clearance were assessed. rCYP (recombinant cytochrome P450) reaction phenotyping indicated that CYP3A4 was responsible for ACP-5862 formation and metabolism. ACP-5862 formation Km (Michaelis constant) and Vmax were 2.78 μM and 4.13 pmol/pmol CYP3A/min, respectively. ACP-5862 intrinsic clearance was 23.6 μL/min per mg. Acalabrutinib weakly inhibited CYP2C8, CYP2C9, and CYP3A4, and ACP-5862 weakly inhibited CYP2C9 and CYP2C19; other cytochrome P450s, UGTs (uridine 5'-diphospho-glucuronosyltransferases), and aldehyde oxidase were not inhibited. Neither parent nor ACP-5862 strongly induced CYP1A2, CYP2B6, or CYP3A4 mRNA. Acalabrutinib and ACP-5862 were substrates of multidrug resistance protein 1 and breast cancer resistance protein but not OATP1B1 or OATP1B3. Our work indicates that ACP-5862 may contribute to clinical efficacy in acalabrutinib-treated patients and illustrates how proactive metabolite characterization allows timely assessment of drug-drug interactions and potential contributions of metabolites to pharmacological activity. SIGNIFICANCE STATEMENT: This work characterized the major metabolite of acalabrutinib, ACP-5862. Its contribution to the pharmacological activity of acalabrutinib was assessed based on covalent Bruton tyrosine kinase binding kinetics, kinase selectivity, and potency in cellular assays. The metabolic clearance and in vitro drug-drug interaction potential were also evaluated for both acalabrutinib and ACP-5862. The current data suggest that ACP-5862 may contribute to the clinical efficacy observed in acalabrutinib-treated patients and demonstrates the value of proactive metabolite identification and pharmacological characterization.
Exposure-response analysis of acalabrutinib and its active metabolite, ACP-5862, in patients with B-cell malignancies
Br J Clin Pharmacol 2022 May;88(5):2284-2296.PMID:34532877DOI:10.1111/bcp.15087.
Aims: Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP-5862) vs. efficacy and safety responses in patients with B-cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. Methods: For exposure-efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression-free survival and tumour regression. For exposure-safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B-cell malignancies. Acalabrutinib and ACP-5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP-5862 to overall efficacy/safety. Results: A total of 573 patients were included (exposure-efficacy analyses, n = 274; exposure-safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration-time curve (AUC24h,ss ) and total active maximal concentration at steady-state (Cmax,ss ) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC24h,ss /Cmax,ss and progression-free survival or tumour regression. Acalabrutinib AUC24h,ss and Cmax,ss were generally comparable across groups regardless of AE incidence. Conclusion: No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B-cell malignancies.
Improved characterization of the pharmacokinetics of acalabrutinib and its pharmacologically active metabolite, ACP-5862, in patients with B-cell malignancies and in healthy subjects using a population pharmacokinetic approach
Br J Clin Pharmacol 2022 Feb;88(2):846-852.PMID:34265100DOI:10.1111/bcp.14988.
This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analysed by nonlinear mixed-effects modelling. Acalabrutinib PK was characterized by a 2-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a 2-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and coadministration of proton-pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.
Evaluation of the Drug-Drug Interaction Potential of Acalabrutinib and Its Active Metabolite, ACP-5862, Using a Physiologically-Based Pharmacokinetic Modeling Approach
CPT Pharmacometrics Syst Pharmacol 2019 Jul;8(7):489-499.PMID:31044521DOI:10.1002/psp4.12408.
Acalabrutinib, a selective, covalent Bruton tyrosine kinase inhibitor, is a CYP3A substrate and weak CYP3A/CYP2C8 inhibitor. A physiologically-based pharmacokinetic (PBPK) model was developed for acalabrutinib and its active metabolite ACP-5862 to predict potential drug-drug interactions (DDIs). The model indicated acalabrutinib would not perpetrate a CYP2C8 or CYP3A DDI with the sensitive CYP substrates rosiglitazone or midazolam, respectively. The model reasonably predicted clinically observed acalabrutinib DDI with the CYP3A perpetrators itraconazole (4.80-fold vs. 5.21-fold observed) and rifampicin (0.21-fold vs. 0.23-fold observed). An increase of two to threefold acalabrutinib area under the curve was predicted for coadministration with moderate CYP3A inhibitors. When both the parent drug and active metabolite (total active components) were considered, the magnitude of the CYP3A DDI was much less significant. PBPK dosing recommendations for DDIs should consider the magnitude of the parent drug excursion, relative to safe parent drug exposures, along with the excursion of total active components to best enable safe and adequate pharmacodynamic coverage.