PHPS1 is a cell permeability, phosphotyrosine analog that selectively inhibits Src-homodomain-containing phosphatases (SHP2) with an IC50 value of 2.1µM and a Ki value of 0.73µM[1]. PHPS1 can inhibit SHP2-dependent cell function and tumor cell line growth[2]. PHPS1 can effectively inhibit TGF-β1-induced epithelial-mesenchymal transition in A549 lung epithelial cells[3]. PHPS1 can alleviate airway inflammation and airway hyperresponsiveness in allergic mice[4].
In vitro, treatment of human tumor cell lines (MDA-MB-435, HCT-15, PC-3, HT-29, NCI-H661 cells) with PHPS1 (30µM) for 6 days inhibited the proliferation and colony formation of human tumor cell lines[5].
In vivo, PHPS1 (3mg/kg) administered intraperitoneally to atherosclerotic (AS) mice for one week reduced the number of atherosclerotic plaques without significantly affecting body weight, serum glucose levels, or lipid metabolism, and inhibited the formation of neointima and the proliferation of smooth muscle cells at the aortic root[6]. PHPS1 (15mg/kg) administered intraperitoneally to pancreatic cancer model mice significantly inhibited tumor growth, with the tumor volume in the monotherapy group reduced by approximately 60% compared to the control group[7].
References:
[1] Ramamoorthy D. Synthesis of small molecule inhibitors targeting signal transduction pathways[J]. 2009.
[2] Kong J, Long Y Q. Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors[J]. RSC Medicinal Chemistry, 2022, 13(3): 246-257.
[3] Liu Y, Guan Y, Shen J, et al. RETRACTED ARTICLE: Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production[J]. Respiratory Research, 2020, 21(1): 161.
[4] Xu C, Wu X, Lu M, et al. Protein tyrosine phosphatase 11 acts through RhoA/ROCK to regulate eosinophil accumulation in the allergic airway[J]. The FASEB Journal, 2019, 33(11): 11706.
[5] Hellmuth K, Grosskopf S, Lum C T, et al. Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking[J]. Proceedings of the National Academy of Sciences, 2008, 105(20): 7275-7280.
[6] Chen J, Cao Z, Guan J. SHP2 inhibitor PHPS1 protects against atherosclerosis by inhibiting smooth muscle cell proliferation[J]. BMC cardiovascular disorders, 2018, 18(1): 72.
[7] Gomes E G, Connelly S F, Summy J M. Targeting the yin and the yang: combined inhibition of the tyrosine kinase c-Src and the tyrosine phosphatase SHP-2 disrupts pancreatic cancer signaling and biology in vitro and tumor formation in vivo[J]. Pancreas, 2013, 42(5): 795-806.
PHPS1是一种细胞通透性、磷酸酪氨酸类似物，能够选择性抑制含Src同源结构域的磷酸酶（SHP2），IC50值为2.1µM，Ki值为0.73µM[1]。PHPS1能够抑制SHP2依赖的细胞功能及肿瘤细胞系的生长[2]。PHPS1能够有效抑制TGF-β1 诱导的肺上皮A549细胞的上皮-间质转化[3]。PHPS1能减轻过敏小鼠的气道炎症和气道高反应性[4]。
在体外，PHPS1（30µM）处理人肿瘤细胞系（MDA-MB-435、HCT-15、PC-3、HT-29、NCI-H661细胞）6天，抑制了人肿瘤细胞系的增殖和集落形成[5]。
在体内，PHPS1（3mg/kg）通过腹腔注射治疗动脉粥样硬化（AS）小鼠1周，减少了小鼠动脉粥样硬化斑块的数量，且对体重、血清葡萄糖水平或脂质代谢无显著影响，抑制了主动脉根部的新生内膜的形成和平滑肌细胞的增殖[6]。PHPS1（15mg/kg）通过腹腔注射治疗胰腺癌模型小鼠，显著抑制了肿瘤生长，单药治疗组小鼠的肿瘤体积较对照组减少了约60%[7]。