TBOPP
目录号 : GC38855
TBOPP is a selective inhibitor of dedicator of cytokinesis (DOCK1, Dock180) that inhibits DOCK1-mediated Rac activation with IC50 of 8.4 μM. TBOPP binds to the DOCK1 DHR-2 domain with Kd of 7.1 μM. TBOPP exhibits anti-tumor activity.
Cas No.:1996629-79-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TBOPP is a selective inhibitor of dedicator of cytokinesis (DOCK1, Dock180) that inhibits DOCK1-mediated Rac activation with IC50 of 8.4 μM. TBOPP binds to the DOCK1 DHR-2 domain with Kd of 7.1 μM. TBOPP exhibits anti-tumor activity.
[1] Hirotada Tajiri, et al. Cell Rep. 2017 May 2;19(5):969-980.
| Cas No. | 1996629-79-8 | SDF | |
| Canonical SMILES | O=C1C=CC(S(=O)(N2CCCC2)=O)=CN1CC(C3=CC=C(C4=CC=CC(C(F)(F)F)=C4)C=C3)=O | ||
| 分子式 | C24H21F3N2O4S | 分子量 | 490.49 |
| 溶解度 | DMSO: 125 mg/mL (254.85 mM) | 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0388 mL | 10.1939 mL | 20.3878 mL |
| 5 mM | 0.4078 mL | 2.0388 mL | 4.0776 mL |
| 10 mM | 0.2039 mL | 1.0194 mL | 2.0388 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % 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.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
TBOPP enhances the anticancer effect of cisplatin by inhibiting DOCK1 in renal cell carcinoma
Mol Med Rep 2020 Aug;22(2):1187-1194.PMID:32626999DOI:10.3892/mmr.2020.11243.
The treatment of renal cell carcinoma (RCC) with chemotherapy remains a challenge; therefore, improving the knowledge of the molecular mechanisms underlying RCC chemoresistance and developing novel therapeutic strategies is important. Dedicator of cytokinesis 1 (DOCK1), the first member of the DOCK family to be discovered, displays various roles during tumorigenesis; however, its role during RCC progression is not completely understood. Therefore, the present study aimed to clarify the function of DOCK1 and 1‑[2‑(3'‑(trifluoromethyl)‑(1,1'‑biphenyl)‑4‑yl)‑2‑oxoethyl]‑5‑pyrrolidinylsulfonyl‑2 (1H)‑pyridone (TBOPP), a DOCK1‑sensitive inhibitor, during RCC development and chemoresistance. The results of CCK‑8 and EdU assay indicated that TBOPP decreased RCC cell viability and proliferation compared with the control group, and sensitized RCC cells to cisplatin. Moreover, RCC cells with high DOCK1 expression levels displayed increased resistance to cisplatin, whereas DOCK1 knockdown enhanced the lethal effects of cisplatin on RCC cells. Furthermore, the results determined by western blotting, CCK‑8 and cell apoptosis assay indicated that TBOPP effectively reduced DOCK1 expression levels compared with the control group, and the TBOPP‑mediated cisplatin sensitizing effect was mediated by DOCK1 inhibition. The present study suggests that DOCK1 plays a vital role in RCC cell chemoresistance to cisplatin; therefore, TBOPP may serve as a novel therapeutic agent for RCC chemoresistance.
Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer
Protein Cell 2022 Nov;13(11):825-841.PMID:35217990DOI:10.1007/s13238-022-00906-6.
Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Decreased juvenile arson and firesetting recidivism after implementation of a multidisciplinary prevention program
J Trauma 2002 Aug;53(2):260-4; discussion 264-6.PMID:12169931DOI:10.1097/00005373-200208000-00012.
Objectives: In 1999, we developed the multidisciplinary Trauma Burn Outreach Prevention Program (TBOPP), which focuses on the medical and societal consequences of firesetting behavior. The basis for this program development was a 17% increase in pediatric burn admissions. The purpose of this study was to determine the value of this trauma burn center prevention program from a financial, clinical, and recidivism perspective. Methods: Juveniles (ages 4-17 years) were enrolled into our 1-day program on the basis of referrals from the county court system, fire departments, schools, and parents. The program's interactive content focuses on the medical, financial, legal, and societal impact of firesetting behavior, with emphasis on individual accountability and responsibility. The court system and fire departments tracked all episodes of firesetting behavior within their respective communities. Arson is defined as behavior with the intent to produce damage, whereas firesetting is defined as having no ill intent. The recidivism rate was determined using fire department and court follow-up records. Follow-up was from 8 months to 2.5 years. A random control group that did not receive TBOPP education (noTBOPP group) with identical entry criteria was used for comparison. Institutional review board approval was obtained. Results: There were 132 juveniles in the TBOPP group (66 arsonists and 66 firesetters) and 102 juveniles in the noTBOPP group (33 arsonists and 66 firesetters). Fifty-nine TBOPP participants had a medical history of behavioral disorders. Property damage for arson averaged $4,040, with additional court costs of $1,135 per incident. Family environment was an independent predictor for risk of repeat offense. The odds ratio for risk of repeat offense in foster care was 17.9 (p < 0.05) as compared with two-parent homes. The recidivism rate was 1 of 32 (<1%) for the TBOPP group and 37 of 102 (36%) for the noTBOPP group (adjusted odds ratio, 0.02; p < 0.001). Conclusion: When compared with the noTBOPP group, TBOPP participants had essentially no recidivism. The financial impact of arson behavior was over $6,000 per incident. The implementation of a juvenile firesetting prevention program has demonstrable benefits to the participants and to society.
Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1
Cell Rep 2017 May 2;19(5):969-980.PMID:28467910DOI:10.1016/j.celrep.2017.04.016.
Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.
The supression of DOCK family members by their specific inhibitors induces the cell fusion of human trophoblastic cells
Biochem Biophys Res Commun 2020 Sep 3;529(4):1173-1179.PMID:32819582DOI:10.1016/j.bbrc.2020.06.138.
Purpose: Among the members of the DOCK family, DOCK1-5 function as guanine-nucleotide exchange factors for small GTPase Rac1, which regulates the actin cytoskeleton. It has been reported that in model organisms the Dock-Rac axis is required for myoblast fusion. We examined the role of DOCK1-5 in trophoblast fusion herein. Methods: We used a quantitative polymerase chain reaction (qPCR) to examine the mRNA expressions of DOCK1-5 and differentiation-related genes, i.e., fusogenic genes, in human trophoblastic cell lines, BeWo and JEG-3. We treated BeWo cells with TBOPP and C21 to inhibit DOCK1 and DOCK5. Cell dynamics and cell fusion were assessed by live imaging and immunostaining. The signaling pathways induced by DOCK1/5 inhibition were examined by western blotting. Results: DOCK1 and DOCK5 were expressed in BeWo cells. The inhibition of DOCK1 or DOCK5 did not prevent the cell fusion induced by forskolin (a common reagent for cell fusion); it induced cell fusion. DOCK1 inhibition induced cell death, as did forskolin. DOCK1 and DOCK5 inhibition for 24 and 48 h increased the expression of the genes ASCT2 and SYNCYTIN2, which code responsive proteins of trophoblast cell fusion, respectively. Conclusion: DOCK1 and DOCK5 inhibition participates in BeWo cell fusion, probably via pathways independent from forskolin-mediated pathways.