PF-3758309
(Synonyms: PF 3758309; PF3758309) 目录号 : GC17214
PF-3758309是 ATP竞争性p21活化激酶4（PAK4）抑制剂，其Kd值为2.7nM，Ki值为18.7nM。
Cas No.:898044-15-0
Sample solution is provided at 25 µL, 10mM.
PF-3758309 is an ATP-competitive p21-activated kinase 4 (PAK4) inhibitor with a Kd value of 2.7nM and a Ki value of 18.7nM[1]. PF-3758309 can induce apoptosis, cytoskeletal remodeling, and inhibit cell proliferation[2]. PF-3758309 can suppress the proliferation of cancer cells[3]. PF-3758309 has the ability to inhibit HIV virus replication[4].
In vitro, pretreatment of patient-derived pancreatic ductal adenocarcinoma cell lines (TKCC-15) with PF-3758309 (2.5–10μM) for 48 hours significantly inhibited cell proliferation and enhanced chemosensitivity[5]. Pretreatment of A549 human lung cancer cells with PF-3758309 (0.1–10μM) for 24 hours significantly suppressed cell migration and invasion capabilities, while downregulating the expression of matrix metalloproteinases MMP-2 and MMP-9[6].
In vivo, oral administration of PF-3758309 (25mg/kg) twice daily to nude mice bearing colorectal cancer cell line xenografts or patient-derived tumor xenografts (PDTX) for 14–56 days significantly inhibited tumor growth and reduced intratumoral drug concentration[7]. Oral administration of PF-3758309 (7.5–30mg/kg) twice daily to nude mice bearing human tumor xenografts (such as HCT116, A549) for 9–18 days significantly suppressed tumor growth and induced tumor cell apoptosis[8].
References:
[1] Huynh N, Liu KH, Yim M, et al. Demonstration and biological significance of a gastrin-P21-activated kinase 1 feedback loop in colorectal cancer cells. Physiol Rep. 2014 Jun 24;2(6):e12048.
[2] Ramos-Alvarez I, Jensen RT. P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades. Am J Physiol Gastrointest Liver Physiol. 2018 Aug 1;315(2):G302-G317.
[3] Dukel M, Fiskin K. Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response. Int J Radiat Biol. 2023;99(2):340-354.
[4] Vargas B, Boslett J, Yates N, et al. Mechanism by Which PF-3758309, a Pan Isoform Inhibitor of p21-Activated Kinases, Blocks Reactivation of HIV-1 Latency. Biomolecules. 2023 Jan 4;13(1):100.
[5] Wang K, Huynh N, Wang X, et al. PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines. Am J Transl Res. 2019 Jun 15;11(6):3353-3364.
[6] Ryu BJ, Lee H, Kim SH, et al. PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-κB, and β-catenin signalings. Mol Cell Biochem. 2014 Apr;389(1-2):69-77.
[7] Bradshaw-Pierce EL, Pitts TM, Tan AC, et al. Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer. Front Pharmacol. 2013 Mar 22;4:22.
[8] Murray BW, Guo C, Piraino J, et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51.
PF-3758309是ATP竞争性p21活化激酶4（PAK4）抑制剂，其Kd值为2.7nM，Ki值为18.7nM[1]。PF-3758309可诱导细胞凋亡、细胞骨架重塑和抑制细胞增殖[2]。PF-3758309可抑制癌细胞的增殖[3]。PF-3758309还具有抑制HIV病毒复制的能力[4]。
在体外，PF-3758309（2.5–10μM）预处理患者来源的胰腺导管腺癌细胞系（TKCC-15）48小时，显著抑制细胞增殖并增强化疗药物敏感性[5]。PF-3758309（0.1–10μM）预处理A549人肺癌细胞24小时，显著抑制细胞迁移和侵袭能力，同时下调基质金属蛋白酶MMP-2和MMP-9的表达[6]。
在体内，PF-3758309（25mg/kg）每日两次口服给药，处理携带结直肠癌细胞系异种移植瘤或患者来源肿瘤异种移植瘤（PDTX）的裸鼠14-56天，显著抑制肿瘤生长并降低瘤内药物浓度[7]。PF-3758309（7.5–30mg/kg）每日两次口服给药，处理携带人肿瘤异种移植瘤（HCT116、A549）的裸鼠9–18天，显著抑制肿瘤生长并诱导肿瘤细胞凋亡[8]。
| Cell experiment [1]: | |
Cell lines | A549 human lung adenocarcinoma cells; H1299 human lung cancer cells |
Preparation Method | A549 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100U/mL penicillin, and 100μg/mL streptomycin at 37°C in a humidified atmosphere of 5% CO₂. A549 cells were treated with PF-3758309 at various concentrations (0.1–10μM) for 24 hours. |
Reaction Conditions | 0.1-10μM; 24h |
Applications | PF-3758309 significantly inhibited the migration and invasion of A549 human lung cancer cells in a dose-dependent manner. PF-3758309 suppressed the phosphorylation of PAK4 (Ser474), CREB (Ser133), and ERK1/2 (Thr202/Tyr204), and inhibited the transcriptional activities of CREB, NF-κB, and β-catenin pathways. This led to the downregulation of MMP-2 and MMP-9 expressions at both mRNA and protein levels. |
| Animal experiment [2]: | |
Animal models | Athymic nude mice bearing human tumor xenografts (HCT116 colorectal carcinoma, A549 lung carcinoma) |
Preparation Method | Mice were orally administered PF-3758309 twice daily (BID) at doses of 7.5-30mg/kg for 9-18 days. Tumor volumes were measured regularly using calipers. For pharmacokinetic/pharmacodynamic (PK/PD) studies, Alzet osmotic minipumps were used to deliver finely controlled drug exposures. |
Dosage form | 7.5-30mg/kg; oral gavage |
Applications | PF-3758309 significantly inhibited tumor growth in multiple human xenograft models, with >70% tumor growth inhibition (TGI) in sensitive models including HCT116 and A549. The plasma EC₅₀ value was determined to be 0.4nM in the most sensitive model. PF-3758309 was not active in DLD1 cells (loss-of-function PAK4 mutation) or cMet-driven GTL16 model. |
References: | |
| Cas No. | 898044-15-0 | SDF | |
| 别名 | PF 3758309; PF3758309 | ||
| 化学名 | N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide | ||
| Canonical SMILES | CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C4(C)C)C(=O)NC(CN(C)C)C5=CC=CC=C5)SC=C2 | ||
| 分子式 | C25H30N8OS | 分子量 | 490.62 |
| 溶解度 | ≥ 24.53 mg/mL in DMSO, ≥ 101.4 mg/mL in EtOH with ultrasonic and warming | 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0382 mL | 10.1912 mL | 20.3824 mL |
| 5 mM | 407.6 μL | 2.0382 mL | 4.0765 mL |
| 10 mM | 203.8 μL | 1.0191 mL | 2.0382 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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