PHPS1

PHPS1 is a cell permeability, phosphotyrosine analog that selectively inhibits Src-homodomain-containing phosphatases (SHP2) with an IC₅₀ value of 2.1µM and a K_i 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 RETRACTED ARTICLE: Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production[J].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.