PF-06463922是一种新型的、具有口服活性的ALK（IC50=15-113nM）和ROS1（Kis=0.025-0.7nM）双重抑制剂。
Cas No.:1454846-35-5
Sample solution is provided at 25 µL, 10mM.
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PF-06463922 is a novel, orally active dual inhibitor of ALK (IC50=15-113nM) and ROS1 (Kis=0.025-0.7nM)[1-2]. PF-06463922 blocks downstream signaling pathways by inhibiting the phosphorylation of ALK and ROS1 kinases. PF-06463922 is used in the treatment of locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC)[3-4].
In vitro, PF-06463922 (0.01-1µM) was used to treat ALK-rearranged non-small cell lung cancer cell lines (such as H3122 and H2228) for 16-96 hours. PF-06463922 significantly induced BIM expression and promoted apoptosis, while simultaneously downregulating NOXA, leading to MCL-1-dependent anti-apoptotic adaptation [5]. PF-06463922 (10nM) treated ALK-positive NSCLC cells (H3122 and H2228 cell lines) for 24-48 hours. PF-06463922 effectively inhibited cell proliferation and induced apoptosis, while also triggering protective autophagy[6].
In vivo, PF-06463922 (5mg/kg; p.o.; daily for 14days) was used to treat C57BL/6 mice bearing orthotopic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer (CRC) liver metastasis models. PF-06463922 significantly reduced the weight of primary tumors and metastases, decreased intratumoral neutrophil accumulation and fibrosis, and inhibited tumor cell proliferation[7]. PF-06463922 (orally administered at 10mg/kg daily for 3 weeks) was used to treat 10-week-old sexually mature male C57BL/6N mice. PF-06463922 reversibly suppressed male fertility, impaired sperm's ability to bind to the zona pellucida, led to abnormal processing of ADAM3, and compromised sperm motility[8].
References:
[1] Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014 Jun 12;57(11):4720-44.
[2] Zou HY, Friboulet L, Kodack DP, et al. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell. 2015 Jul 13;28(1):70-81.
[3] Solomon BJ, Liu G, Felip E, et al. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol. 2024 Oct 10;42(29):3400-3409.
[4] Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029.
[5] Martín F, Alcon C, Marín E, Morales-Sánchez P, et al. Novel selective strategies targeting the BCL-2 family to enhance clinical efficacy in ALK-rearranged non-small cell lung cancer. Cell Death Dis. 2025 Mar 20;16(1):194.
[6] Lu C, Yu R, Zhang C, et al. Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC. Cell Death Discov. 2022 Apr 22;8(1):221.
[7] Nielsen SR, Strøbech JE, Horton ER, et al. Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade. Nat Commun. 2021 Jun 7;12(1):3414.
[8] Oyama Y, Shimada K, Miyata H, et al. Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice. Andrology. 2025 Oct;13(7):1891-1900.
PF-06463922是一种新型的、具有口服活性的ALK（IC50=15-113nM）和ROS1（Kis=0.025-0.7nM）双重抑制剂[1-2]。PF-06463922通过抑制ALK和ROS1激酶的磷酸化来阻断下游信号通路。PF-06463922可用于ALK阳性的局部晚期或转移性非小细胞肺癌（NSCLC）的治疗[3-4]。
在体外，PF-06463922（0.01-1μM）处理ALK重排的非小细胞肺癌细胞系（如H3122和H2228）16-96小时。PF-06463922显著诱导BIM表达并促进细胞凋亡，同时下调NOXA导致MCL-1依赖性抗凋亡适应 [5]。PF-06463922（10nM）处理ALK阳性的非小细胞肺癌细胞（H3122和H2228细胞系）24-48小时。PF-06463922有效抑制细胞增殖并诱导细胞凋亡，同时诱导保护性自噬 [6]。
在体内，PF-06463922（每日口服5mg/kg；持续14天）用于处理携带原位胰腺导管腺癌（PDAC）或结直肠癌（CRC）肝转移模型的C57BL/6小鼠。PF-06463922显著降低了原发肿瘤和转移灶的重量，减少了肿瘤内中性粒细胞的积累和纤维化，并抑制了肿瘤细胞增殖[7]。PF-06463922（每日口服10mg/kg；持续3周）用于处理10周龄性成熟的C57BL/6N雄性小。PF-06463922可逆地抑制了雄性生育能力，、降低精子与透明带的结合能力、导致ADAM3加工异常并损害精子运动能力[8]。
| Cell experiment [1]: | |
Cell lines | H3122 and H2228 cells (ALK-positive non-small cell lung cancer cell lines) |
Preparation Method | H3122 and H2228 cells were cultured in RPMI-1640 supplemented with 10% FBS. The cells were treated with PF-06463922 at 10nM for 24-48 hours. |
Reaction Conditions | 10nM; 24-48h. |
Applications | PF-06463922 effectively inhibited the proliferation and induced apoptosis in ALK-positive NSCLC cells. PF-06463922 activated protective autophagy, which could gradually lead to decreased cytotoxicity. However, when combined with the autophagy inhibitor chloroquine (CQ), PF-06463922-induced autophagy was inhibited, and apoptosis was significantly enhanced via activation of the Foxo3a/Bim axis. |
| Animal experiment [2]: | |
Animal models | Sexually mature male C57BL/6N mice |
Preparation Method | Ten-week-old male mice were treated orally with PF-06463922 (10mg/kg) for 3 weeks. Some mice were euthanized for analysis immediately after the treatment, while others were allowed a 3-week recovery period after drug discontinuation before analysis. |
Dosage form | 10mg/kg; p.o.; daily for 3 weeks. |
Applications | PF-06463922 administration for 3 weeks reversibly suppressed male fertility. PF-06463922 impaired the maintenance of the epididymal initial segment epithelium, decreased the levels of epididymal proteins (OVCH2, RNASE10, ADAM28), and led to abnormal processing of the sperm membrane protein ADAM3. Consequently, sperm from treated mice lost their ability to bind to the zona pellucida, and sperm motility was significantly impaired. All these effects, including fertility, recovered 3 weeks after discontinuation of the treatment. |
References: | |
| Cas No. | 1454846-35-5 | SDF | |
| 别名 | 劳拉替尼; PF-06463922 | ||
| Canonical SMILES | FC1=CC([C@H](OC2=C(N)N=CC(C3=C(C#N)N(C)N=C3CN4C)=C2)C)=C(C4=O)C=C1 | ||
| 分子式 | C21H19FN6O2 | 分子量 | 406.41 |
| 溶解度 | ≥ 20.3mg/mL 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 | 2.4606 mL | 12.3028 mL | 24.6057 mL |
| 5 mM | 492.1 μL | 2.4606 mL | 4.9211 mL |
| 10 mM | 246.1 μL | 1.2303 mL | 2.4606 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。
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