Identification of novel small-molecule inhibitors targeting menin–MLL interaction, repurposing the antidiarrheal loperamide

Abstract

Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 μM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 μM, 0.69 ± 0.07 μM and 0.66 ± 0.05 μM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.

Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins

“…There are other inhibitors of the Menin–MLL1 interaction, including macrocyclic peptidomimetic compound MCP-1 [ 118 ], a peptidomimetic compound 25 [ 62 ], VTP-50469 [ 63 ] [ 64 ], neomycin [ 65 ], tobramycin [ 65 ], loperamide [ 66 ], DCZ_M123 [ 67 ], DC-YM21 [ 66 ], and cytisine derivative 1a [ 68 ].…”

Drug Repurposing for Targeting Acute Leukemia With KMT2A (MLL)—Gene Rearrangements

“…In this context, there have been successful de novo designed small molecule inhibitors of the MLL-menin interaction, such as members of the thienopyrimidine class ( Shi et al, 2012 ; Senter et al, 2015 ; Borkin et al, 2016 ). The crystal structures of the inhibitors MI-2-2 and MIV-6R were used in scaffold hopping calculations that as a result suggested loperamide, an antidiarrheal drug used in acute and chronic diarrhea as well as in ileostomy, as a possible inhibitor of the interaction between MLL and menin ( Yue et al, 2016 ). Similarly to molecules that disrupt the MLL-menin interaction, histone deacetylase (HDAC) inhibitors also affect the transcription-regulatory machinery governing the epigenetic changes that drive leukemogenesis.…”

Computer-Aided Drug Design in Epigenetics

“…As a shape-based three dimensional structure superposition method, it has been extensively used to generate potential alternatives of known compounds based on the bioisosteric replacement of core motif within molecules (Sun et al, 2012 ; Lamberth, 2017 ). In 2016, Yue et al applied a shape-based scaffold hopping approach to reposition approved drugs targeting the Menin-MLL1 interaction (Yue et al, 2016 ). In the study, reported bioactive conformations of representative Menin-MLL1 inhibitors MI-2-2 and MIV-6R (PDB code 4GQ4 and 4GO8, respectively) were used as query (Shi et al, 2012 ; He et al, 2014 ).…”