VTP50469 is a small-molecule inhibitor of the Menin-MLL protein-protein interaction with a Ki of 104 pM.
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]。
参考文献:
[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.
| 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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参考文献: [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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