PF 3758309 dihydrochloride 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 dihydrochloride can induce apoptosis, cytoskeletal remodeling, and inhibit cell proliferation[2]. PF 3758309 dihydrochloride can suppress the proliferation of cancer cells[3]. PF 3758309 dihydrochloride 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 dihydrochloride (2.5–10μM) for 48 hours significantly inhibited cell proliferation and enhanced chemosensitivity[5]. Pretreatment of A549 human lung cancer cells with PF 3758309 dihydrochloride (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 dihydrochloride (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 dihydrochloride (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 dihydrochloride 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 dihydrochloride, 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 dihydrochloride 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 dihydrochloride, 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 dihydrochloride 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 dihydrochloride 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 dihydrochloride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 dihydrochloride可诱导细胞凋亡、细胞骨架重塑和抑制细胞增殖[2]。PF 3758309 dihydrochloride可抑制癌细胞的增殖[3]。PF 3758309 dihydrochloride还具有抑制HIV病毒复制的能力[4]。
在体外，PF 3758309 dihydrochloride（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 dihydrochloride（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 dihydrochloride（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 dihydrochloride（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]。