PP 1 is a novel, potent, and selective Src family tyrosine kinase inhibitor. PP 1 effectively inhibits the phosphorylation of Lck (IC50=5nM) and Fyn (IC50= 6nM) to block T-cell receptor signaling pathways. PP 1 can be used in research related to cancers (such as small cell lung cancer and leukemia) as well as T-cell immune signal transduction[1-4].
In vitro, pretreatment of NMuMG/E9 mouse mammary epithelial cells with PP 1 (10μM) for 30min, followed by stimulation with TGF-β1 (1-5ng/mL) for 1-2 days. PP 1 significantly inhibited the occurrence of epithelial-mesenchymal transition (EMT), while preventing alterations in cell morphology, focal adhesion formation, and the activation of Smad2/3[5]. Pretreatment of human coronary artery smooth muscle cells (HCASMCs) and Swiss 3T3 cells with PP 1 (0.1–10μM) for 15min–4h, followed by stimulation with PDGF-BB (10–15ng/mL) for 4–20h. PP 1 significantly inhibited cell migration and proliferation, while reducing the tyrosine phosphorylation level of PDGFβ receptors[6].
In vivo, a single intraperitoneal injection of PP 1 (1.5mg/kg) was administered to treat the transient middle cerebral artery occlusion (tMCAO) mouse model. PP 1 significantly rescued the FUNDC1-mediated neuronal mitophagy dysfunction caused by I/R injury[7]. Daily intraperitoneal injection of PP 1 (2mg/kg) was administered to the unilateral ureteral obstruction (UUO)-induced renal fibrosis mouse model for 3-14 days. PP 1 significantly reduced the deposition of extracellular matrix and inhibited the activation of renal interstitial fibroblasts, thereby ameliorating the development of renal fibrosis[8].
References:
[1] Zan L, Zhang X, Xi Y, et al. Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion. Neuroscience. 2014 Mar 14;262:118-28.
[2] Warmuth M, Simon N, Mitina O, et al. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood. 2003 Jan 15;101(2):664-72.
[3] Karni R, Mizrachi S, Reiss-Sklan E, et al. The pp60c-Src inhibitor PP1 is non-competitive against ATP. FEBS Lett. 2003 Feb 27;537(1-3):47-52.
[4] Kantibekovna SL, Wang S, Kang H, et al. Selective antitumor and apoptosis‑inducing effects of the Src inhibitor PP1 in human tongue squamous cell carcinoma cells. Int J Oncol. 2026 May;68(5):64.
[5] Maeda M, Shintani Y, Wheelock MJ, et al. Src activation is not necessary for transforming growth factor (TGF)-beta-mediated epithelial to mesenchymal transitions (EMT) in mammary epithelial cells. PP1 directly inhibits TGF-beta receptors I and II. J Biol Chem. 2006 Jan 6;281(1):59-68.
[6] Waltenberger J, Uecker A, Kroll J, et al. A dual inhibitor of platelet-derived growth factor beta-receptor and Src kinase activity potently interferes with motogenic and mitogenic responses to PDGF in vascular smooth muscle cells. A novel candidate for prevention of vascular remodeling. Circ Res. 1999 Jul 9;85(1):12-22.
[7] Tang T, Hu LB, Ding C, et al. Src inhibition rescues FUNDC1-mediated neuronal mitophagy in ischaemic stroke. Stroke Vasc Neurol. 2024 Aug 27;9(4):367-379.
[8] Yan Y, Ma L, Zhou X, et al. Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int. 2016 Jan;89(1):68-81.
PP 1是一种新型的高效、选择性Src家族酪氨酸激酶抑制剂，PP 1有效抑制Lck（IC50=5nM）和Fyn（IC50=6nM）的磷酸化来阻断T细胞受体信号通路。PP 1可用于癌症（如小细胞肺癌、白血病）以及T细胞免疫信号传导的相关研究[1-4]。
在体外，PP 1（10μM）预处理NMuMG/E9小鼠乳腺上皮细胞30min，随后以TGF-β1（1-5ng/ml）刺激1-2天，显著抑制上皮间质转化（EMT）的发生，同时阻止细胞形态改变、黏着斑形成及Smad2/3的激活[5]。PP 1（0.1–10μM）预处理人冠状动脉平滑肌细胞（HCASMCs）及Swiss 3T3细胞15min–4h，随后以PDGF-BB（10–15ng/mL）刺激4–20h，显著抑制细胞的迁移与增殖，同时降低PDGFβ受体的酪氨酸磷酸化水平[6]。
在体内，PP 1（1.5mg/kg；单次）腹腔注射于处理短暂性大脑中动脉闭塞（tMCAO）小鼠模型。PP 1显著挽救了由I/R损伤引起的FUNDC1介导的神经元线粒体自噬功能障碍[7]。PP 1（2mg/kg；每日一次）腹腔注射于单侧输尿管梗阻（UUO）诱导的肾纤维化小鼠模型3-14天。PP 1显著减少了细胞外基质的沉积，抑制了肾间质成纤维细胞的激活，从而减轻了肾纤维化的发生发展[8]。