ASK120067
(Synonyms: ASK120067) 目录号 : GC62402
ASK120067 (ASK120067) 是一种有效的口服活性 EGFRT790M (IC50:0.3 nM) 抑制剂，选择性高于 EGFRWT (IC50:6.0 nM)。 ASK120067是用于非小细胞肺癌（NSCLC）研究的第三代EGFR-TKI。
Cas No.:1934259-00-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ASK120067 is a potent and orally active inhibitor of EGFRT790M (IC50:0.3 nM) with selectivity over EGFRWT (IC50:6.0 nM). ASK120067 is a third-generation EGFR-TKI for the research of non-small cell lung cancer (NSCLC)[1].
In the in vitro kinase assay ASK120067 potently inhibits the EGFR L858R/T790M and EGFR T790M resistant mutants with IC50 values of 0.3 nM and 0.5 nM, respectively, as well as the EGFRexon19del sensitizing mutant (IC50= 0.5 nM). The 50 of ASK120067 against wild-type EGFR (EGFRWT) is 6 nM[1].ASK120067 selectively inhibits the growth of EGFR-mutant cell lines and exhibits potent antiproliferative activity in the mutant EGFR NSCLC cells, with IC50 values of 12 nM, 6 nM and 2 nM against NCI-H1975 (T790M mutation), PC-9, and HCC827 cells (sensitizing mutations), respectively. However, it shows moderate or weak anti-growth activities in A431, LoVo and A549 cells (EGFRWT), with IC50 values ranging from 338 nM to 1541 nM[1].ASK120067 (0.1-100 nM) inhibits the phosphorylation of EGFR at Tyrosine residue 1068 and its downstream signaling proteins AKT and ERK in NCI-H1975 cells (EGFRL858R/T790M) even at low dosage (0.1-1 nM). Additionally, ASK120067 inhibits p-EGFR and p-Akt and p-erk in EGFR WT A431 cell until the concentration reaches 10 to 100 nM[1].
ASK120067 (oral gavage; 5-20 mg/kg; once daily; 21 days) results in significantly regressed tumor growth, with a tumor growth inhibition (TGI) rate of 85.7%, and administration of 10 mg/kg ASK120067 causes dramatic tumor shrinkage with a TGI rate of 99.3%, exhibiting a similar potency with Osimertinib[1].
[1]. Tao Zhang, et al. Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance. Mol Cancer. 2020 May 13;19(1):90.
| Cas No. | 1934259-00-3 | SDF | |
| 别名 | ASK120067 | ||
| 分子式 | C29H32ClN7O2 | 分子量 | 546.06 |
| 溶解度 | DMSO : 100 mg/mL (183.13 mM; Need ultrasonic) | 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 | 1.8313 mL | 9.1565 mL | 18.313 mL |
| 5 mM | 0.3663 mL | 1.8313 mL | 3.6626 mL |
| 10 mM | 0.1831 mL | 0.9157 mL | 1.8313 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。
Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance
Mol Cancer 2020 May 13;19(1):90.PMID:32404161DOI:10.1186/s12943-020-01202-9.
Background: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention. Methods: We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan. Results: We identified compound ASK120067 as a novel inhibitor of EGFR T790M, with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo. Conclusions: Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.
ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK
Front Pharmacol 2022 Dec 15;13:1071114.PMID:36588692DOI:10.3389/fphar.2022.1071114.
Hyperactivation of Bruton's tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent in vitro inhibitory efficacy against Bruton's tyrosine kinase protein and interleukin-2-inducible T cell kinase protein via covalent binding. In cell-based assays, ASK120067 dose-dependently suppressed Bruton's tyrosine kinase phosphorylation and exhibited anti-proliferation potency by inducing apoptosis in numerous B-lymphoma cells. Meanwhile, it caused growth arrest and induced the apoptosis of T-cell leukemia cells by attenuating interleukin-2-inducible T cell kinase activation. Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK.
Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study
J Thorac Oncol 2022 Oct;17(10):1205-1215.PMID:35659581DOI:10.1016/j.jtho.2022.05.011.
Introduction: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. Methods: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Results: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. Conclusions: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. Clinical trial information: NCT03502850.
Development of an LC-MS/MS method for quantifying ASK120067, a novel mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) as well as its main metabolite in human plasma and its application in a pharmacokinetic study
J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 1;1162:122488.PMID:33360679DOI:10.1016/j.jchromb.2020.122488.
ASK120067, an oral irreversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), is formulated for the management of patients with non-small cell lung cancer (NSCLC) who harbor T790M resistant and EGFR active mutations. Two rapid and high-throughput methods based on liquid chromatography-tandem mass spectrometry to detect ASK120067 and its primary metabolite CCB4580030 in human plasma were developed and applied in the clinical trials. A protein precipitation method using acetonitrile coupled with a gradient elution separation in a BEH C18 column (1.7 µm, 2.1 × 50 mm) was used to process plasma and separation analytes. The chromatographic separation was performed on the mobile phase of 5 mM ammonium acetate in water with 0.1% formic acid (A) and acetonitrile (B), and the flow rate was 0.4 mL/min. The multiple reaction monitoring (MRM) mode was selected to monitor the precursor-to-product ion transitions of m/z 546.2 → m/z 431.2 for ASK120067 and m/z 532.1 → m/z 420.2 for CCB4580030 at the positive ionization mode. The precision and accuracy of the two methods for ASK1200067 and CCB4580030 were within acceptable range for the linear range in 5.00-5000 ng/mL and 0.500-500 ng/mL, respectively. Further stabilities for the two analytes and internal standard were also investigated covered the entire experimental process beginning from harvesting whole blood to plasma extraction and analysis. ASK120067 was then administered without issue onto a dose-escalation, the first-in-human Phase I clinical trial in Chinese NSCLC patients to determine the pharmacokinetics of oral ASK120067 administration.