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Proton Pump Inhibitors Selectively Suppress MLL Rearranged Leukemia Cells via Disrupting MLL1-WDR5 Protein-Protein Interaction

Proton Pump Inhibitors Selectively Suppress MLL Rearranged Leukemia Cells via Disrupting MLL1-WDR5 Protein-Protein Interaction

Wei-Lin Chen, Dong-Dong Li, Xin Chen, Ying-Zhe Wang, Jun-Jie Xu, Zheng-Yu Jiang, Qi-Dong You, Xiao-Ke Guo

Eur J Med Chem. 2020 Feb 15;188:112027.

PMID: 31923859

Abstract:

Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells. Mechanism study showed Rabeprazole down-regulated the transcription of MLL-FPs related Hox and Meis1 genes and effectively inhibited MLL1 H3K4 methyltransferase (HMT) activity in MV4-11 cells bearing MLL-AF4 fusion protein. Displacement of MLL1 probe from WDR5 protein suggested that Rabeprazole may inhibit MLL1 HMT activity through disturbing MLL1-WDR5 protein-protein interaction. Moreover, other proton pump inhibitors (PPIs) also indicated the inhibition activity of MLL1-WDR5. Preliminary SARs showed the structural characteristics of PPIs were also essential for the activities of MLL1-WDR5 inhibition. Our results indicated the drug reposition of PPIs for MLL-rearranged leukemias and provided new insight for further optimization of targeting MLL1 methyltransferase activity, the MLL1-WDR5 interaction or WDR5.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
ALP1163685300	Rabeprazole Related Compound A		1163685-30-0 (free acid)	Price

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