SNDX-5613
(Synonyms: SNDX-5613) 目录号 : GC39508
SNDX-5613是一种有效的选择性Menin-MLL（混合谱系白血病）相互作用抑制剂，Ki值为0.149nM。
Cas No.:2169919-21-3
Sample solution is provided at 25 µL, 10mM.
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SNDX-5613 is a potent and selective inhibitor of Menin-MLL (mixed lineage leukemia) interaction with a Ki value of 0.149nM[1]. SNDX-5613 can inhibit the proliferation and survival of MLL-rearranged leukemia cells and treat relapsed or refractory acute myeloid leukemia (AML)[2].
In vitro, SNDX-5613 (250nM) treatment of UBTF-TD mutant AML cell lines (MV4-11, RL048, Kasumi-1 cells) significantly altered the overall gene expression of cells, down-regulated important downstream target genes of Menin-MLL interaction (such as MEIS1, FLT3, PBX3, MEF2C genes), and up-regulated differentiation markers (such as HOXA9, CD11b, MNDA)[4].
In vivo, oral administration of SNDX-5613 (50mg/kg) to mice bearing AML cell xenografts for 2 weeks significantly reduced tumor burden and prolonged survival of the mice. The effect was even better when combined with OTX015[5].
References:
[1] Toldra J, Fernandez-Llamazares A I, Auderset M E, et al. American Association for Cancer Research Virtual Annual Meeting I. April 27-28, 2020[J]. Drugs of the Future, 2020, 45(6).
[2] Fiskus W, Boettcher S, Daver N, et al. Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)[J]. Blood cancer journal, 2022, 12(1): 5.
[3] Mohnani R. New Treatment Opportunity for Acute Myeloid Leukemias Harbouring a UBTF Tandem Duplication[D]. , 2023.
[4] Fiskus W, Mill C P, Birdwell C, et al. Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1[J]. Blood cancer journal, 2023, 13(1): 53.
SNDX-5613是一种有效的选择性Menin-MLL（混合谱系白血病）相互作用抑制剂，Ki值为0.149nM[1]。SNDX-5613能够抑制MLL重排白血病细胞的增殖和存活，治疗复发或难治性急性髓系白血病（AML）[2]。
在体外，SNDX-5613（250nM）处理UBTF-TD变异的AML细胞系（MV4-11、RL048、Kasumi-1细胞），显著改变了细胞的整体基因表达，下调了Menin-MLL相互作用的重要下游靶基因（例如MEIS1、FLT3、PBX3、MEF2C基因），上调了分化标志物（例如HOXA9、CD11b、MNDA）[4]。
在体内，SNDX-5613（50mg/kg）通过口服治疗AML细胞异种移植小鼠2周，显著降低了小鼠体内的肿瘤负荷，延长了小鼠生存期，与OTX015联合治疗效果更佳[5]。
| Cell experiment [1]: | |
Cell lines | Acute myeloid leukemia (AML) cells (MV4-11, RL048, and Kasumi-1 cells) |
Preparation Method | To investigate the effect of SNDX-5613 on global gene expression, primary AML cells harboring the UBTF-TD alteration were co-cultured with mesenchymal stromal cells (MSCs) and treated with 250nM SNDX-5613, or DMSO on days 1, 4, 7, and 10. Appropriate splitting and refreshing of the medium was carried out in between. Cells were harvested for sorting via fluorescence-activated cell sorting (FACS) on days 7 and 12 of treatment with the aim of obtaining pure AML cells. For gene expression analysis, reads were mapped to the human genome (Hg38) using STAR (v2.2.0c). Only reads that mapped to unique genomic locations (MAPQ>10) were used for downstream analysis and differentially expressed genes between the treated groups were identified using DESeq version 2. |
Reaction Conditions | 250nM; 2-12 days |
Applications | SNDX-5613 treatment substantially changed global gene expression of UBTF-TD AMLs, including downregulation of important downstream target genes that depend upon the Menin-MLL interaction and upregulation of differentiation markers. |
| Animal experiment [2]: | |
Animal models | NSG mice |
Preparation Method | NSG mice were engrafted with luciferized patient-derived MLL-AF9+FLT3-TKD expressing Acute myeloid leukemia (AML) cells and monitored. Mice were randomized and treated with vehicle, 50mg/kg SNDX-5613 (oral, daily × 5 days) and/or 30mg/kg OTX015 (oral, daily × 5 days) for 2 weeks. Tumor burden was measured by total photon counts measured by bioluminescence imaging. |
Dosage form | 50mg/kg; 5 days; p.o. |
Applications | SNDX-5613 alone and in combination with OTX015 or GNE-781 significantly inhibited tumor growth and prolonged survival in MLL-rearranged AML mouse models. |
References: | |
| Cas No. | 2169919-21-3 | SDF | |
| 别名 | SNDX-5613 | ||
| Canonical SMILES | O=C(N(CC)C(C)C)C1=CC(F)=CC=C1OC2=CN=CN=C2N3CC4(CCN(C[C@H]5CC[C@H](NS(=O)(CC)=O)CC5)CC4)C3 | ||
| 分子式 | C32H47FN6O4S | 分子量 | 630.82 |
| 溶解度 | DMSO: 41.67 mg/mL (66.06 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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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 |
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