SHP099 is a highly potent, selective, orally bioavailable SHP2 inhibitor, with an IC50 value of 0.071μM [1]. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism [2]. SHP099, widely used to inhibit the in vitro proliferation of various cancer cells, has been employed as an anti-cancer agent in mouse tumor xenograft models[3].
In vitro, SHP099 significantly inhibited the proliferation of PC9 cells and PC9GR cells within 24 hours, with IC50 values of 7.536 and 8.900μM, respectively[4]. Treatment with 20μM SHP099 for one week significantly inhibited the phosphorylation of ERK protein in synovial mesenchymal stem cells (SMSCs), promoted the expression of SOX9 and COL2, and reduced the expression of the COL10 without affecting cell viability[5]. Treatment with 5µM SHP099 for 3 days significantly promoted the accumulation of proteins related to induced cell death (including cleaved caspase-3) in human umbilical vein endothelial cells (HUEVCs), and reduced the decrease of pro-survival proteins (including Survivin), significantly inducing cell death[6].
In vivo, SHP099 treatment via intraperitoneal injection at 5mg/kg/day for 17 days inhibited the tumor growth of CT-26 cell xenograft BALB/c mice, without affecting body weight of mice[7]. A single intraperitoneal injection of 15mg/kg of SHP099 for 12 hours significantly inhibited the pulmonary inflammatory response in the acute lung injury mouse model and increased the survival rate of the mice[8].
References:
[1] Wu J, Zhang H, Zhao G, et al. Allosteric inhibitors of SHP2: an updated patent review (2015-2020)[J]. Current Medicinal Chemistry, 2021, 28(19): 3825-3842.
[2] Wang M, Li T, Ouyang Z, et al. SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis[J]. Iscience, 2022, 25(4).
[3] Sang Y, Hou Y, Cheng R, et al. Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2–mediated signaling[J]. Neuro-oncology, 2019, 21(11): 1423-1435.
[4] Xia L, Yang F, Wu X, et al. SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness[J]. Cancer Cell International, 2021, 21(1): 337.
[5] Sun Z, Xu X, Lv Z, et al. Intraarticular injection of SHP2 inhibitor SHP099 promotes the repair of rabbit full-thickness cartilage defect[J]. Journal of Orthopaedic Translation, 2022, 32: 112-120.
[6] Wang Y, Salvucci O, Ohnuki H, et al. Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth[J]. EMBO Molecular Medicine, 2021, 13(7): e14089.
[7] Zhao M, Guo W, Wu Y, et al. SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 304-315.
[8] Ye S, Zuo B, Xu L, et al. Inhibition of SHP2 by the small molecule drug SHP099 prevents lipopolysaccharide-induced acute lung injury in mice[J]. Inflammation, 2023, 46(3): 975-986.
SHP099是一种高效、选择性、口服生物可利用的SHP2抑制剂，IC50值为0.071μM[1]。SHP099通过同时结合N端SH2、C端SH2和蛋白酪氨酸磷酸酶结构域的界面，以变构机制抑制SHP2活性[2]。SHP099被广泛用于抑制多种癌细胞的体外增殖，并作为抗癌剂应用于小鼠肿瘤异种移植模型[3]。
在体外，SHP099处理24小时可显著抑制PC9和PC9GR细胞增殖，IC50值分别为7.536μM和8.900μM[4]。20μM的SHP099处理滑膜间充质干细胞（SMSCs）一周能抑制ERK蛋白磷酸化，促进SOX9和COL2表达，并降低COL10的表达且不影响细胞活力[5]。5µM的SHP099处理人脐静脉内皮细胞（HUVECs）3天可促进凋亡相关蛋白（包括cleaved caspase-3）积累，减少促存活蛋白（如Survivin）水平，显著诱导细胞死亡[6]。
在体内，CT-26细胞异种移植BALB/c小鼠每日腹腔注射SHP099（5mg/kg/day；持续17天）可抑制肿瘤生长且不影响体重[7]。急性肺损伤小鼠模型单次腹腔注射15mg/kg剂量的SHP099（12小时）能显著抑制肺部炎症反应并提高生存率[8]。