VTP50469
目录号 : GC61376
VTP50469 is a small-molecule inhibitor of the Menin-MLL protein-protein interaction with a Ki of 104 pM.
Cas No.:2169916-18-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
MOLM13 cells, RS4;11 lymphoblast cells |
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Preparation Method |
Cells are treated for 2 and 7 days with VTP50469 or DMSO followed by RNA-seq analysis. |
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Reaction Conditions |
330 nM; 2 and 7 days |
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Applications |
VTP50469 treatment leads to rapid downregulation of MLL fusion-driven gene expression. |
| Animal experiment [2]: | |
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Animal models |
Female NSG mice(7-9 week-old) |
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Preparation Method |
The mice(carrying MV4;11-FUW-Luc-mCh-Puro cells ) were randomized into four treatment groups (n=10) based on body weight. The groups included a vehicle control and three VTP50469 groups (15, 30, 60 mg/kg BID). Treatment began on day 5 and continued for 28 days. |
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Dosage form |
15 /30 /60mg/kg;p.o.;23days |
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Applications |
VTP50469 treatment(30 and 60 mg/kg) had a surprisingly extended survival advantage in mice. |
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References: [1]. Krivtsov AV, Evans K, et,al. A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. Cancer Cell. 2019 Dec 9;36(6):660-673.e11. doi: 10.1016/j.ccell.2019.11.001. PMID: 31821784; PMCID: PMC7227117. |
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VTP50469 is a small-molecule inhibitor of the Menin-MLL protein-protein interaction with a Ki of 104 pM. VTP50469 has potently anti-leukemia activity[1-4].
VTP50469 led to a profound reduction in cell proliferation in a concentrationdependent manner in MLL-r cell lines, besides, VTP50469 treatment(330 nM; 2 and 7 days) leads to rapid downregulation of MLL fusion-driven gene expression[3].
VTP50469 (30 and 60 mg/kg;p.o.;23days) had a surprisingly extended survival advantage in MLL-r Acute Leukemia patient-derived xenograft (PDX) mice[3]. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias[5].
VTP50469是Menin-MLL蛋白-蛋白相互作用的小分子抑制剂,Ki值为104 pM. VTP50469具有强大的抗白血病活性[1-4]。
VTP50469导致MLL-r细胞系中细胞增殖以浓度依赖的方式显著减少,此外,VTP50469处理(330 nM; 2 and 7 days)导致MLL融合驱动基因表达的快速下调[3]。
VTP50469(30和60 mg/kg; ;p.o.;23days)能够让MLL-r急性白血病患者来源的异种移植(PDX)小鼠中延长生存期[3]。用VTP50469治疗可显著延长移植NUP98-NSD1和NUP98-JARID1A白血病小鼠的存活时间[5]。
References:
[1]. Ishchenko A, Liu Z, et al.Structure-based design technology contour and its application to the design of renin inhibitors. J Chem Inf Model. 2012 Aug 27;52(8):2089-97. doi: 10.1021/ci200605k. Epub 2012 Jul 25. PMID: 22805048.
[2].Janssens DH, Meers MP, et al. Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia. Nat Genet. 2021 Nov;53(11):1586-1596. doi: 10.1038/s41588-021-00941-9. Epub 2021 Oct 18. PMID: 34663924; PMCID: PMC8571097.
[3]. Krivtsov AV, Evans K, et al. A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. Cancer Cell. 2019 Dec 9;36(6):660-673.e11. doi: 10.1016/j.ccell.2019.11.001. PMID: 31821784; PMCID: PMC7227117.
[4]. Andrei V. Krivtsov, et al. Abstract 4958: VTP50469 is a novel, orally available menin-MLL1 inhibitor effective against MLL-rearranged and NPM1-mutant leukemia. Cancer Resceach. July 2018.Volume 78, Issue 13 Supplement.
[5]. Heikamp EB, Henrich JA, et al. The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. Blood. 2022 Feb 10;139(6):894-906. doi: 10.1182/blood.2021012806. PMID: 34582559; PMCID: PMC8832476.
| Cas No. | 2169916-18-9 | SDF | |
| Canonical SMILES | O=C(N(C(C)C)C(C)C)C1=CC(F)=CC=C1OC2=CN=CN=C2N3CC4(CCN(C[C@H]5CC[C@H](NS(=O)(C)=O)CC5)CC4)C3 | ||
| 分子式 | C32H47FN6O4S | 分子量 | 630.82 |
| 溶解度 | DMSO: 125 mg/mL (198.15 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 | 1.5852 mL | 7.9262 mL | 15.8524 mL |
| 5 mM | 0.317 mL | 1.5852 mL | 3.1705 mL |
| 10 mM | 0.1585 mL | 0.7926 mL | 1.5852 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。
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia
Cancer Cell 2019 Dec 9;36(6):660-673.e11.PMID:31821784DOI:10.1016/j.ccell.2019.11.001.
Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.
The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML
Blood 2022 Feb 10;139(6):894-906.PMID:34582559DOI:10.1182/blood.2021012806.
Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.