Ziftomenib is a highly selective and orally active inhibitor of the Menin-MLL (mixed lineage leukemia) interaction used to treat relapsed or refractory acute myeloid leukemia (AML)[1, 2]. Ziftomenib can inhibit the proliferation and survival of MLL-rearranged leukemia cells by blocking the binding of Menin protein to MLL fusion protein[3].
In vitro, Ziftomenib (150nM) treatment of AML cell lines (OCI-AML3, MOLM13, MV411 cells) induced transcriptional downregulation of MEIS1, PBX3, FLT3 and BCL2[4].
In vivo, oral treatment of AML cell xenograft mice with Ziftomenib (75mg/kg) significantly reduced the tumor burden in mice and prolonged the survival of mice[5].
References:
[1] Zhao J, Dong X, Che J. Ziftomenib (KO-539): a potent and selective Menin inhibitor for the treatment of recurrent or refractory acute myeloid leukemia[M]//Drug Discovery Stories. Elsevier, 2025: 455-466.
[2] Wang E S, Issa G C, Erba H P, et al. Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): A multicentre, open-label, multi-cohort, phase 1 trial[J]. The Lancet Oncology, 2024, 25(10): 1310-1324.
[3] Dhiman S, Dhillon V, Balasubramanian S K. Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions[J]. Cancers, 2024, 16(22): 3743.
[4] Rausch J, Dzama M M, Dolgikh N, et al. Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax[J]. Haematologica, 2023, 108(10): 2837.
[5] Fiskus W, Daver N, Boettcher S, et al. Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1[J]. Leukemia, 2022, 36(11): 2729-2733.
Ziftomenib是一种高选择性具口服活性的Menin-MLL（混合谱系白血病）相互作用抑制剂，用于治疗复发或难治性急性髓系白血病（AML）[1, 2]。Ziftomenib能够通过阻断Menin蛋白与MLL融合蛋白的结合，抑制MLL重排白血病细胞的增殖和存活[3]。
在体外，Ziftomenib（150nM）处理AML细胞系（OCI-AML3、MOLM13、MV411细胞），均诱导了MEIS1、PBX3、FLT3和BCL2的转录下调[4]。
在体内，Ziftomenib（75mg/kg）通过口服治疗AML细胞异种移植小鼠，显著降低了小鼠体内的肿瘤负荷，延长小鼠生存期[5]。