GlpBio

PF-064639223X 积分

目录号: GC14794纯度: >99.50%同义词: 劳拉替尼; PF-06463922
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。
PF-06463922
Cas No.: 1454846-35-5
规格价格库存数量操作
5mg¥496.00现货
1
10mg¥802.00现货
1
25mg¥1,666.00现货
1
50mg¥2,492.00现货
1
100mg¥3,381.00现货
1
10mM (in 1mL DMSO)¥601.00现货
1
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产品描述 Description

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]。

实验参考方法 Experimental Reference Method

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:
[1] 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.
[2] 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.

产品文档 Product Documents

Purity:>99.50%

化学性质Chemical Properties

CAS 号
1454846-35-5
同义词
劳拉替尼; PF-06463922
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 g/mol
溶解性
≥ 20.3mg/mL in DMSO
保存条件
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°C，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。

计算工具摩尔浓度 / 稀释 / 分子量 / 单位换算 / 体内配方 / 溶解度

g/mol