ASLAN003
(Synonyms: ASLAN003) 目录号 : GC38463
A DHODH inhibitor
Cas No.:1035688-66-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ASLAN003 is an inhibitor of dihydroorotate dehydrogenase (DHODH; IC50 = 35 nM).1 It inhibits the proliferation of MOLM-14 and KG-1 acute myeloid leukemia (AML) cells (IC50s = 0.582 and 0.382 ?M, respectively), as well as induces apoptosis in the same cells when used at concentrations of 0.5 and 1 ?M. ASLAN003 (1, 2, and 4 ?M) induces differentiation in bone marrow cells isolated from patients with AML or myelodysplastic syndrome (MDS). It improves survival in a patient-derived xenograft (PDX) mouse model of AML when administered at a dose of 50 mg/kg.
1.Zhou, J., Quah, J.Y., Ng, Y., et al.ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemiaHaematologica105(9)2286-2297(2020)
| Cas No. | 1035688-66-4 | SDF | |
| 别名 | ASLAN003 | ||
| Canonical SMILES | O=C(C1=CC=CN=C1NC2=C(F)C=C(C3=CC=CC(OC)=C3)C=C2F)O | ||
| 分子式 | C19H14F2N2O3 | 分子量 | 356.32 |
| 溶解度 | DMSO: 130 mg/mL (364.84 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 | 2.8065 mL | 14.0323 mL | 28.0647 mL |
| 5 mM | 0.5613 mL | 2.8065 mL | 5.6129 mL |
| 10 mM | 0.2806 mL | 1.4032 mL | 2.8065 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。
ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia
Haematologica 2020 Sep 1;105(9):2286-2297.PMID:33054053DOI:10.3324/haematol.2019.230482.
Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.
Discovery of potent human dihydroorotate dehydrogenase inhibitors based on a benzophenone scaffold
Eur J Med Chem 2022 Dec 5;243:114737.PMID:36115209DOI:10.1016/j.ejmech.2022.114737.
Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC50 values of 0.1-0.8 μM. Supplementation of exogenous uridine rescued the cell viability of 7d-treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising hDHODH inhibitor 7d with potential activities against some tumors.