| 规格 | 价格 | 库存 | 数量 |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
|
| 靶点 |
TrkA (IC50 = 1.1 nM); TrkC (IC50 = 5.1 nM); TrkB (IC50 = 7.8 nM)
CH7057288 inhibits the growth of TRK fusion-positive cell lines, but not that of TRK-negative cell lines, and exhibits selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays. As a downstream signaling of TRK fusion, CH7057288 inhibits the E2F and mitogen-activated protein kinase (MAPK) pathways[1]. |
|---|---|
| 体外研究 (In Vitro) |
CH7057288 抑制 TRK 融合阳性细胞系的生长，但不抑制 TRK 阴性细胞系的生长，并且在无细胞激酶测定中对 TRKA、TRKB 和 TRKC 表现出选择性抑制活性。作为 TRK 融合的下游信号传导，CH7057288 抑制 E2F 和丝裂原激活蛋白激酶 (MAPK) 通路[1]。
CH7057288 能以剂量依赖的方式（0.01–0.1 µM，处理2小时）有效抑制TRK融合阳性癌细胞系（CUTO-3、KM12-Luc、MO-91）中TRK的自磷酸化。它还能抑制这些细胞中下游信号蛋白PLCγ1、ERK和Akt的磷酸化。[1] CH7057288 选择性抑制TRK融合阳性细胞系（CUTO-3、KM12-Luc、MO-91）的增殖，IC₅₀值在个位数到十位数纳摩尔范围内（例如，CUTO-3为9.0 ± 1.9 nM，KM12-Luc为4.4 ± 0.31 nM，MO-91为1.4 ± 2.0 nM）。相比之下，TRK阴性细胞系（NCI-H1299、HCT116）不敏感（IC₅₀ >1,000 nM）。在一个包含272个癌细胞系的大规模筛选面板中，TRK融合阳性细胞系在对CH7057288最敏感的细胞中高度富集。[1] CH7057288 对野生型（WT）TRKA和临床报告的G667C-TRKA突变体具有相当的抑制效力（生化IC₅₀：WT = 0.0015 µM，G667C = 0.00068 µM；细胞IC₅₀：WT = 0.0047 µM，G667C = 0.0018 µM）。然而，其对G595R-TRKA突变体的活性降低（生化IC₅₀ = 0.083 µM；细胞IC₅₀ = 3.0 µM）。[1] 用1 µM CH7057288处理CUTO-3和KM12-Luc细胞4和24小时的基因表达分析（RNA-seq）显示，TRK融合下游的MAPK和E2F通路被显著抑制。Western blot分析证实了CyclinD1、E2F1、p-Rb和MAPK靶基因（DUSP6、SPRY4、ETV1）的下调。[1] |
| 体内研究 (In Vivo) |
TRK融合阳性细胞皮下植入的异种移植肿瘤模型显示出对肿瘤生长的强大体内抑制作用。此外，CH7057288 在模拟脑转移的颅内植入模型中显着诱导肿瘤消退并提高无事件生存率。在所有三种模型中，CH7057288 均诱导强烈的肿瘤生长抑制，在 CUTO-3 和 MO-91 中肿瘤显着消退。 CH7057288 的暴露量随剂量而变化。由于终末半衰期相对较短（3至5小时），给药后24小时血浆浓度下降至Tmax的十分之几至百分之一[1]。
在TRK融合阳性细胞（CUTO-3、KM12-Luc、MO-91）的皮下异种移植模型中，每日口服CH7057288（0.3–30 mg/kg，持续10-28天）能诱导强效的肿瘤生长抑制和显著的肿瘤消退。在有效剂量下未观察到显著的体重下降。[1] 在使用CUTO-3-Luc细胞的颅内植入模型（模拟中枢神经系统转移）中，每日口服CH7057288（30 mg/kg，持续30天）与溶剂对照组相比，显著降低了颅内生物发光信号（表明肿瘤消退）并延长了无事件生存期。[1] 在表达MPRIP-WT-TRKA或MPRIP-G667C-TRKA融合的皮下NIH3T3异种移植模型中，CH7057288（30 mg/kg，每日一次，持续7天）对WT和G667C突变体肿瘤诱导了相似程度的肿瘤消退。相比之下，表达G595R-TRKA突变体的肿瘤对CH7057288以及entrectinib和larotrectinib均产生耐药。[1] |
| 酶活实验 |
使用均相时间分辨荧光（HTRF）法测定了CH7057288对TRKA、TRKB、TRKC以及一组其他激酶（如INSR、ALK、EGFR、FGFR2、HER2、JAK2、KDR、MET、ROS1、SRC、AKT1、CDK1、CHK1、ERK1、PKA、PKCα）的抑制活性。对于酪氨酸激酶，使用铕标记的抗磷酸酪氨酸抗体测量酶对底物肽的活性。对于丝氨酸/苏氨酸激酶，使用荧光偏振（FP）法测量活性。计算酶抑制活性并确定IC₅₀值。[1]
使用针对403种非突变和65种突变激酶的竞争性结合实验（KINOMEscan）进一步评估了激酶选择性。在100 nM浓度下，CH7057288仅与除TRKA、TRKB和TRKC之外的6种激酶结合。[1] |
| 细胞实验 |
将所示浓度的 CH7057288 应用于 TRK 融合阳性癌细胞系 CUTO-3、KM12-Luc 和 MO-91 两小时。细胞裂解后进行蛋白质印迹。
对于细胞活力/增殖实验，将细胞接种于球体培养板或384孔微孔板中，用连续稀释的CH7057288处理4或7天。使用基于ATP检测的发光法对活细胞数量进行定量，并计算IC₅₀值。[1] 对于信号抑制研究，用CH7057288（例如，0.01–0.1 µM，2小时）处理TRK融合阳性细胞系。裂解细胞后，通过Western blot分析TRK、PLCγ1、ERK和Akt的磷酸化水平，以及下游蛋白（CyclinD1、E2F1、Rb、DUSP6、SPRY4、ETV1）的表达水平。[1] 对于突变TRK活性，用CH7057288处理稳定表达MPRIP-WT-、G667C-或G595R-TRKA融合的NIH3T3细胞（通过慢病毒感染和嘌呤霉素筛选建立），并分析细胞活力（同上）和TRK磷酸化（Western blot）。[1] 对于RNA测序分析，用1 µM CH7057288或DMSO处理CUTO-3和KM12-Luc细胞4和24小时。提取总RNA，制备mRNA文库并进行测序。识别差异表达基因并进行通路富集分析。[1] |
| 动物实验 |
For subcutaneous xenograft models, female SCID mice (for MO-91 model) or BALB/c nude mice (for other models) were used. TRK fusion-positive cancer cells (e.g., CUTO-3, KM12-Luc, MO-91) were suspended in HBS or PBS, mixed with Matrigel (for some models), and injected subcutaneously into the right flank. When tumor volumes reached approximately 200–300 mm³, mice were randomized into groups (n=5 or 7). CH7057288, suspended in an unspecified vehicle, was administered orally once daily at doses ranging from 0.3 to 30 mg/kg for 10 to 28 days. Tumor dimensions were measured twice weekly, and volume was calculated (length × width² / 2). For pharmacodynamic analysis, tumors were resected at specified times post-dose for Western blot or RNA analysis. [1]
For the intracranial tumor model, CUTO-3-Luc cells were transplanted intracranially into nude mice. Seventeen days post-transplantation, mice were randomized into two groups (n=7) based on intracranial bioluminescence. CH7057288 (30 mg/kg) or vehicle was administered orally once daily for 30 days. Intracranial tumor burden was monitored via bioluminescence imaging after intraperitoneal injection of luciferin. Event-free survival (events defined as death, >20% body weight loss, or motility defect) was recorded. [1] For mutant TRK xenograft studies, NIH3T3 cells expressing MPRIP-WT-, G667C-, or G595R-TRKA fusions were injected subcutaneously into mice. When tumors were established, mice were treated orally once daily for 7 days with CH7057288 (30 mg/kg), entrectinib (150 mg/kg), or larotrectinib (60 mg/kg). Tumor volumes were monitored. [1] |
| 药代性质 (ADME/PK) |
Plasma pharmacokinetics of CH7057288 were assessed in tumor-bearing mice after multiple dosing (11 days). Plasma samples were collected pre-dose and at 0.5, 2, 4, 7, and 24 hours post-dose. CH7057288 exhibited dose-dependent plasma exposure. The terminal half-life was relatively short (3–5 hours), with plasma concentration at 24 hours post-dose dropping to approximately a few tenths to a hundredth of the Cmax. At 4 hours post-dose, a 1 mg/kg dose achieved sub-micromolar plasma concentrations, which correlated with strong TRK suppression in tumors. [1]
CH7057288 is a potential substrate of P-glycoprotein (P-gp) based on a Caco-2 permeability assay, which may influence its blood-brain barrier penetration. [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In the in vivo efficacy studies conducted, daily oral administration of CH7057288 at efficacious doses (up to 30 mg/kg for 10-30 days) did not cause significant body weight loss in mice bearing subcutaneous or intracranial xenografts. [1]
In the KM12-Luc subcutaneous model, body weight steadily decreased in the vehicle-treated group but recovered in the CH7057288-treated groups concomitant with tumor growth inhibition. [1] Histological analysis of tumors from CH7057288-treated mice showed decreased Ki-67 (proliferation marker) staining and increased TUNEL (apoptosis marker) staining. [1] |
| 参考文献 | |
| 其他信息 |
CH7057288 is a novel, selective pan-TRK inhibitor with a benzofuran chemical structure distinct from other reported TRK inhibitors (e.g., entrectinib, larotrectinib). [1]
An X-ray crystal structure of the TRKA kinase domain in complex with CH7057288 (PDB ID: 5WR7) revealed that the compound binds in the DFG-out/αC-helix out conformation, forming hydrogen bonds with Met592 and Lys544. This binding mode allows a favorable sulfur-π interaction with the Cys667 residue in the G667C-TRKA mutant, explaining its retained potency against this mutant. In contrast, the G595R mutation causes steric repulsion. [1] CH7057288 suppresses oncogenic signaling downstream of TRK fusions, primarily inhibiting the MAPK pathway initially, followed by suppression of the E2F pathway, leading to cell cycle arrest and apoptosis. [1] The compound demonstrated activity against a clinically reported TRKA resistance mutation (G667C) that confers resistance to entrectinib and larotrectinib, highlighting its potential therapeutic utility in overcoming such resistance. [1] CH7057288 showed efficacy in an intracranial tumor model, suggesting potential utility against TRK fusion-positive cancers with central nervous system involvement. [1] |
| 分子式 |
C32H31N3O5S
|
|---|---|
| 分子量 |
569.670646905899
|
| 精确质量 |
569.2
|
| 元素分析 |
C, 67.47; H, 5.49; N, 7.38; O, 14.04; S, 5.63
|
| CAS号 |
2095616-82-1
|
| 相关CAS号 |
2095616-82-1
|
| PubChem CID |
131839646
|
| 外观&性状 |
Off-white to yellow solid powder
|
| LogP |
5.3
|
| tPSA |
127
|
| 氢键供体(HBD)数目 |
2
|
| 氢键受体(HBA)数目 |
7
|
| 可旋转键数目(RBC) |
6
|
| 重原子数目 |
41
|
| 分子复杂度/Complexity |
1210
|
| 定义原子立体中心数目 |
0
|
| InChi Key |
DCGOHGQJHJXBGW-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C32H31N3O5S/c1-18-14-20(30(37)34-31(2,3)4)16-21(33-18)10-8-19-9-12-24-26(15-19)40-29-27(24)28(36)23-13-11-22(35-41(7,38)39)17-25(23)32(29,5)6/h9,11-17,35H,1-7H3,(H,34,37)
|
| 化学名 |
N-tert-butyl-2-[2-[8-(methanesulfonamido)-6,6-dimethyl-11-oxonaphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methylpyridine-4-carboxamide
|
| 别名 |
CH7057288; CH-7057288; CH 7057288
|
| HS Tariff Code |
2934.99.03.00
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| 溶解度 (体外实验) |
DMSO: ~100 mg/mL (~175.5 mM)
|
|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.75 mg/mL (4.83 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 27.5 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80 +，混匀；然后加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7554 mL | 8.7770 mL | 17.5540 mL | |
| 5 mM | 0.3511 mL | 1.7554 mL | 3.5108 mL | |
| 10 mM | 0.1755 mL | 0.8777 mL | 1.7554 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
|
|
|
|
InvivoChem的所有产品仅用于作科学研究，不面向患者销售
Copyright 2020 InvivoChem LLC | All Rights Reserved 粤ICP备20063088号-1
COA
粤公网安备 44011102003439号
463611831
