DT-061
目录号 : GC34562
DT-061（SMAP）是一种蛋白磷酸酶2A（PP2A）的口服生物活性激活剂，能够用于KRAS（Kirsten rat sarcoma viral oncogene，一种鼠类肉瘤病毒癌基因）突变和MYC（myelocytomatosis oncogene，骨髓细胞瘤癌基因）驱动的肿瘤的相关研究。
Cas No.:1809427-19-7
Sample solution is provided at 25 µL, 10mM.
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DT-061 (SMAP) is an orally administered bioactive activator of protein phosphatase 2A (PP2A) that can be used to study tumors driven by KRAS (Kirsten rat sarcoma viral oncogene, a murine sarcoma virus oncogene) mutations and MYC (myelocytomatosis oncogene, myeloid cell tumor oncogene)[1, 2]. PP2A is an important intracellular regulatory protein, and its dysregulation is associated with the development and progression of various cancers[3]. DT-061 can disrupt the Golgi apparatus and endoplasmic reticulum, as well as lipid synthesis associated with these structures[4].
In vitro, treatment of KRAS mutant H441 and H358 cell lines with DT-061 (5, 10μM) for 3 weeks significantly inhibited cell colony formation and induced intracellular caspase-3/7 activation[5]. Treatment of MDA-MB-231 cells with DT-061 (5μM) for 24h, in combination with calmidazolium, significantly induced apoptosis and intracellular caspase-3/7 activation[6].
In vivo, oral administration of DT-061 (5mg/kg) to mice with H358 or H441 cell xenografts for 4 weeks significantly inhibited tumor growth, with better efficacy when combined with AZD6244. DT-061 also inhibited the expression of p-AKT (protein kinase B, PKB) and MYC in mice[5]. Oral administration of DT-061 (5mg/kg) to mice with heterotopic heart transplantation prolonged survival and suppressed the inflammatory immune response in the transplanted organs[7].
References:
[1] Brautigan D L, Farrington C, Narla G. Targeting protein phosphatase PP2A for cancer therapy: development of allosteric pharmaceutical agents[J]. Clinical Science, 2021, 135(13): 1545-1556.
[2] Farrington C C. Targeted Degradation of the MYC Oncogene Using PP2A-B56alpha Selective Small Molecule Modulators of Proteinphosphatase 2A as a Therapeutic Strategy for Treating Myc-Driven Cancers[M]. Case Western Reserve University, 2020.
[3] Seshacharyulu P, Pandey P, Datta K, et al. Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer[J]. Cancer letters, 2013, 335(1): 9-18.
[4] Vit G, Duro J, Rajendraprasad G, et al. Chemogenetic profiling reveals PP2A‐independent cytotoxicity of proposed PP2A activators iHAP1 and DT‐061[J]. The EMBO Journal, 2022, 41(14): e110611.
[5] Kauko O, O’Connor C M, Kulesskiy E, et al. PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells[J]. Science translational medicine, 2018, 10(450): eaaq1093.
[6] Manoharan G B, Okutachi S, Abankwa D. Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells[J]. PLoS One, 2022, 17(5): e0268635.
[7] Zhou X, Xu Q, Li W, et al. Protein phosphatase 2A activation promotes heart transplant acceptance in mice[J]. Transplantation, 2024, 108(3): e36-e48.
DT-061（SMAP）是一种蛋白磷酸酶2A（PP2A）的口服生物活性激活剂，能够用于KRAS（Kirsten rat sarcoma viral oncogene，一种鼠类肉瘤病毒癌基因）突变和MYC（myelocytomatosis oncogene，骨髓细胞瘤癌基因）驱动的肿瘤的相关研究[1, 2]。PP2A是细胞内一种重要的调控蛋白，其活性失常与多种癌症的发生发展有关[3]。DT-061能够破坏高尔基体和内质网，以及与这些结构相关的脂质合成[4]。
在体外，DT-061（5, 10μM）处理KRAS突变型H441和H358细胞系3周，显著抑制了细胞克隆形成，诱导了细胞内caspase-3/7激活[5]。DT-061（5μM）处理MDA-MB-231细胞24h，在与calmidazolium联合使用的条件下，显著诱导了细胞凋亡和细胞内caspase-3/7激活[6]。
在体内，DT-061（5mg/kg）通过口服治疗H358细胞或H441细胞异种移植小鼠4周，显著抑制了肿瘤体积生长，与AZD6244联合用药的疗效更好，还能够抑制小鼠体内p-AKT（蛋白激酶B，PKB）和MYC的表达[5]。DT-061（5mg/kg）通过口服治疗异位心脏移植模型小鼠，延长了小鼠的存活时间，抑制了移植器官的炎症免疫反应[7]。
| Cell experiment [1]: | |
Cell lines | KRAS-mutant H441 and H358 cell lines |
Preparation Method | Clonogenic assay of H441 and H358 cells treated with increasing doses of DT-061 (5μM and 10μM), AZD6244 (200nM and 1μM), or the combination of DT-061 and AZD6244 for 3 weeks |
Reaction Conditions | 5, 10μM; 3 weeks |
Applications | Both DT-061 and AZD6244 showed dose-dependent inhibition of colony growth as single agents in both of the cell lines. In addition, doses of DT-061 and AZD6244 that alone did not affect colony growth resulted in a very apparent combinatorial activity. |
| Animal experiment [1]: | |
Animal models | Male BALB/c nu/nu mice |
Preparation Method | H358 or H441 cells were injected into the right flank of 6- to 8-week-old male BALB/c nu/nu mice. When tumor volumes reached an average of 100mm3, mice were randomized to treatment groups, and tumor volume was assessed by caliper measurement every other day throughout the study. Mice were treated by oral gavage with vehicle control, DT-061 (5mg/kg), AZD6244 (25mg/kg), or the combination of DT-061 (5mg/kg) and AZD6244 (25mg/kg) for 4 weeks. The body weights of mice were recorded weekly, and the percentage of body weights during treatment was calculated as weight at each time point/initial weight × 100. Animals were observed for signs of toxicity (mucous diarrhea, abdominal stiffness, or weight loss). Blood and tumor tissue were harvested 2 hours after the final dose of the treatment study. Tumors were both formalin-fixed for IHC and snap-frozen in liquid nitrogen for immunoblotting. |
Dosage form | 5mg/kg; 4 weeks; p.o. |
Applications | Assessed by inhibition of the tumor volume, both DT-061 and AZD6244 showed single-agent activity, but their combination was significantly more efficient than either of the compounds alone. Treatment with DT-061 resulted in suppression of both p-AKT (Protein Kinase B, PKB) and MYC (myelocytomatosis oncogene). |
References: | |
| Cas No. | 1809427-19-7 | SDF | |
| Canonical SMILES | O=S(C1=CC=C(OC(F)(F)F)C=C1)(N[C@H]2[C@H](O)[C@@H](N3C4=C(C=CC=C4)OC5=CC=CC=C35)CCC2)=O | ||
| 分子式 | C25H23F3N2O5S | 分子量 | 520.52 |
| 溶解度 | DMSO : 125 mg/mL (240.14 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 1.9212 mL | 9.6058 mL | 19.2116 mL |
| 5 mM | 384.2 μL | 1.9212 mL | 3.8423 mL |
| 10 mM | 192.1 μL | 960.6 μL | 1.9212 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。
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