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]。