SHP099
(Synonyms: SHP-099游离) 目录号 : GC44887
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。
Cas No.:1801747-42-1
Sample solution is provided at 25 µL, 10mM.
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]。
| Cell experiment [1]: | |
Cell lines | PC9 cells |
Preparation Method | The PC9 cells were all cultured in Dulbecco’s Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS), 100U/mL penicillin and 100mg/mL streptomycin. The cells were cultured at 37℃ and 5% CO2. 2×103 cells were inoculated into each well of a 96-well plate, and 200µL of the medium was added to each well. The cells were incubated with different concentrations of SHP099 (0, 0.625, 1.25, 2.5, 5, 10, and 20μM) for 24h. 50µL of MTT solution was added to the bottom of each well, and the cells were incubated for 4 hours. The absorbance was measured at 490nm using a microplate reader. |
Reaction Conditions | 0, 0.625, 1.25, 2.5, 5, 10, and 20μM; 24h |
Applications | SHP099 significantly inhibited the viability of PC9 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Female BALB/c mice |
Preparation Method | Female BALB/c mice (6-8 weeks old) were housed in a specific pathogen-free (SPF) facility with a 12-hour daily cycle, and had free access to food and water. CT-26 cells were inoculated subcutaneously into BALB/c mice (1×106). The tumor size was measured every day after inoculation, and tumor size was calculated as 0.5×length×width2. Mice with similar tumor sizes were randomly divided into 5 groups and received PBS, 5-Fu, or SHP099. SHP099 was administered intraperitoneally at 5mg/kg daily, and anti-PD-1 antibody was administered intraperitoneally at 5mg/kg every 3 days. After 17 days, the mice were sacrificed and the tumor tissues were collected for analysis. |
Dosage form | 5mg/kg/day for 17 days; i.p. |
Applications | SHP099 treatment inhibited the tumor growth of CT-26 cell xenograft BALB/c mice, and caused the shrinking, sparse arrangement and fragmentation of tumor cells. |
References: | |
| Cas No. | 1801747-42-1 | SDF | |
| 别名 | SHP-099游离 | ||
| Canonical SMILES | ClC1=C(Cl)C(C2=NC=C(N3CCC(C)(N)CC3)N=C2N)=CC=C1 | ||
| 分子式 | C16H19Cl2N5 | 分子量 | 352.3 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,DMSO:PBS(pH 7.2) (1:2): 0.33 mg/ml,Ethanol: 10 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8385 mL | 14.1924 mL | 28.3849 mL |
| 5 mM | 567.7 μL | 2.8385 mL | 5.677 mL |
| 10 mM | 283.8 μL | 1.4192 mL | 2.8385 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
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Quality Control & SDS
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