Ensartinib (X-396)
(Synonyms: X-396) 目录号 : GC33190
An ALK inhibitor
Cas No.:1370651-20-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | For viability experiments, cells are seeded in 96-well plates at 25%-33% confluency and exposed to drugs.The human lung adenocarcinoma cell lines H3122 and H2228 are treated with Ensartinib (10, 30, 100, 300 and 1000 nM). SUDHL-1 lymphoma cells are treated with Ensartinib (5, 10, 30, 100 and 300 nM). SY5Y neuroblastoma cells are treated with Ensartinib (30, 100, 300 and 1000 nM). At 72 hours post Ensartinib addition, Cell Titer Blue Reagent is added and fluorescence is measured on a Spectramax spectrophotometer. All experimental points are set up in hextuplicate replicates and are performed at least two independent times. IC50s are calculated using GraphPad Prism version 5 for Windows. The curves are fit using a nonlinear regression model with a log (inhibitor) vs. response formula[1]. |
Animal experiment: | Mice[1] Nude mice (nu/nu) are injected with H3122 cells. Once tumors reach an average volume of 450 mm3, a total of 27 athymic mice harboring H3122 tumors are randomized and dosed via oral gavage with 25mg/kg Ensartinib (X-396) or the control vehicle. Two, five, and fifteen hours after the single treatment (3 tumors/timepoint/group), mice are sacrificed and serum is collected for assessment of drug concentration using an LC-MS based bioanalytical method. |
References: [1]. Lovly CM, et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinaseinhibitors. Cancer Res. 2011 Jul 15;71(14):4920-31. | |
Ensartinib is a potent and selective inhibitor of anaplastic lymphoma kinase (ALK; IC50 < 0.4 nM in a KINOMEscan kinase activity assay).1 It reduces ALK autophosphorylation and inhibits endogenous ALK phosphorylation and activation of downstream targets ERK and Akt in H3122 cells. Ensartinib reduces growth of H3122 lung cancer cells harboring gain-of-function ALK-fusion proteins (IC50 = 15 nM) but has no effect on cell growth driven by other mutant kinases or that of non-cancerous HepG2 cells. Ensartinib, at a dose of 25 mg/kg, reduces H3122 xenograft growth with no effect on body weight in nude mice. It is also brain-permeable to a concentration of 65 nM.
1.Lovly, C.M., Heuckmann, J.M., de Stanchina, E., et al.Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitorsCancer Res.71(14)4920-4931(2011)
| Cas No. | 1370651-20-9 | SDF | |
| 别名 | X-396 | ||
| Canonical SMILES | O=C(C1=NN=C(N)C(O[C@@H](C2=C(Cl)C=CC(F)=C2Cl)C)=C1)NC3=CC=C(C(N4C[C@@H](C)N[C@@H](C)C4)=O)C=C3 | ||
| 分子式 | C26H27Cl2FN6O3 | 分子量 | 561.44 |
| 溶解度 | Soluble in DMSO | 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 | 1.7811 mL | 8.9057 mL | 17.8113 mL |
| 5 mM | 0.3562 mL | 1.7811 mL | 3.5623 mL |
| 10 mM | 0.1781 mL | 0.8906 mL | 1.7811 mL |
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动物数量 | 只 |
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Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme
Cancers (Basel) 2020 Mar 28;12(4):813.PMID:32231067DOI:10.3390/cancers12040813.
Ensartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs), which play major roles in multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). Accumulation studies showed that ensartinib is a potent inhibitor of ABCB1 and ABCG2 transporters. Additionally, incubation experiments with recombinant CYPs showed that ensartinib significantly inhibits CYP3A4 and CYP2C9. Subsequent molecular docking studies confirmed these findings. Drug combination experiments demonstrated that ensartinib synergistically potentiates the antiproliferative effects of daunorubicin, mitoxantrone, and docetaxel in ABCB1, ABCG2, and CYP3A4-overexpressing cellular models, respectively. Advantageously, ensartinib's antitumor efficiency was not compromised by the presence of MDR-associated ABC transporters, although it acted as a substrate of ABCB1 in Madin-Darby Canine Kidney II (MDCKII) monolayer transport assays. Finally, we demonstrated that ensartinib had no significant effect on the mRNA-level expression of examined transporters and enzymes in physiological and lung tumor cellular models. In conclusion, ensartinib may perpetrate clinically relevant pharmacokinetic DDIs and modulate ABCB1-, ABCG2-, and CYP3A4-mediated MDR. The in vitro findings presented here will provide a valuable foundation for future in vivo investigations.
Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study
Clin Cancer Res 2018 Jun 15;24(12):2771-2779.PMID:29563138DOI:10.1158/1078-0432.CCR-17-2398.
Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of Ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.
Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial
JAMA Oncol 2021 Nov 1;7(11):1617-1625.PMID:34473194DOI:10.1001/jamaoncol.2021.3523.
Importance: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC). Objective: To compare Ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor. Design, setting, and participants: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC. Interventions: Patients were randomized (1:1) to Ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily. Main outcomes and measures: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC. Results: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with Ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the Ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the Ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with Ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with Ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with Ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (Ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (Ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (Ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals. Conclusions and relevance: In this randomized clinical trial, Ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC. Trial registration: ClinicalTrials.gov Identifier: NCT02767804.
Targeting ALK Rearrangements in NSCLC: Current State of the Art
Front Oncol 2022 Apr 6;12:863461.PMID:35463328DOI:10.3389/fonc.2022.863461.
Anaplastic lymphoma kinase (ALK) alterations in non-small cell lung cancer (NSCLC) can be effectively treated with a variety of ALK-targeted drugs. After the approval of the first-generation ALK inhibitor crizotinib which achieved better results in prolonging the progression-free survival (PFS) compared with chemotherapy, a number of next-generation ALK inhibitors have been developed including ceritinib, alectinib, brigatinib, and Ensartinib. Recently, a potent, third-generation ALK inhibitor, lorlatinib, has been approved by the Food and Drug Administration (FDA) for the first-line treatment of ALK-positive (ALK+) NSCLC. These drugs have manageable toxicity profiles. Responses to ALK inhibitors are however often not durable, and acquired resistance can occur as on-target or off-target alterations. Studies are underway to explore the mechanisms of resistance and optimal treatment options beyond progression. Efforts have also been undertaken to develop further generations of ALK inhibitors. This review will summarize the current situation of targeting the ALK signaling pathway.
Effects and mechanism of Ensartinib (X-396) on the adhesion and metastasis of non-small cell lung cancer cells
Pharmazie 2019 Sep 1;74(9):543-546.PMID:31484594DOI:10.1691/ph.2019.9461.
The current study aimed to investigate the inhibitory effect and mechanism of ensartinib on adhesion, invasion and migration of non-small cell lung cancer (NSCLC) cells, including H460 and A549. Cell adhesion test, scratch test and Transwell cell invasion test were used to detect cell adhesion, migration and invasion. RT-PCR was used to detect the expression of MMP-2 and MMP-9 in H460 and A549 cells. Western blot was used to detect the expression of MMP-2 and MMP-9 proteins, ERK signaling pathway related proteins and p-Akt. Our data showed that ensartinib inhibited adhesion, invasion and migration of H460 and A549 cells in a concentration-dependent manner (P < 0.05). Ensartinib decreased the expression of MMP-2 and MMP-9 in H460 and A549 cells (P < 0.01). It also downregulated the expression of MMP-2 and MMP-9 in H460 and A549 cells, and inhibited the expression of Ras, p-c-Raf, p-ERK 1/2 and p-Akt upstream in a concentration- and time-dependent manner. Ensartinib inhibits the adhesion, invasion and migration of NSCLC cells, and such effect is related to downregulation of MMP-2 and MMP-9 expression, inhibition of ERK signaling pathway and p-Akt expression.