Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 188, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.112027
Keywords
Leukemias; MLL fusion proteins; Proton pump inhibitors; MLL1 HMT activity; MLL1-WDR5 interaction
Categories
Funding
- National Natural Science Foundation of China [81872799, 81502915, 81573346, 81773639]
- Natural Science Foundation of Jiangsu Province of China [BK 20191321]
- Fundamental Research Funds for the Central Universities [2632018ZD14]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZCX201611]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2015ZX09101032, 2017ZX09302003, 2018ZX09711002-003-006]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- 111 Project [B16046]
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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. (C) 2020 Elsevier Masson SAS. All rights reserved.
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