ABSTRACT
Histone H3 lysine 36 (H3K36) methylation is a typical epigenetic histone modification that is involved in various biological processes such as DNA transcription, repair and recombination in vivo. Mutations, translocations, and aberrant gene expression associated with H3K36 methyltransferases have been implicated in different malignancies such as acute myeloid leukemia, lung cancer, multiple myeloma, and others. Herein, we provided a comprehensive overview of the latest advances in small molecule inhibitors targeting H3K36 methyltransferases. We analyzed the structures and biological functions of the H3K36 methyltransferases family members. Additionally, we discussed the potential directions for future development of inhibitors targeting H3K36 methyltransferases.
Subject(s)
Antineoplastic Agents , Enzyme Inhibitors , Histone-Lysine N-Methyltransferase , Neoplasms , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Histone-Lysine N-Methyltransferase/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Histones/metabolism , Molecular Structure , AnimalsABSTRACT
WD repeat-containing protein 5 (WDR5) is a member of the WD40 protein family, and it is widely involved in various biological activities and not limited to epigenetic regulation in vivo. WDR5 is also involved in the initiation and development of many diseases and plays a key role in these diseases. Since WDR5 was discovered, it has been suggested as a potential disease treatment target, and a large number of inhibitors targeting WDR5 have been discovered. In this review, we discussed the development of inhibitors targeting WDR5 over the years, and the biological mechanisms of these inhibitors based on previous mechanistic studies were explored. Finally, we describe the development potential of inhibitors targeting WDR5 and prospects for further applications.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Antibodies, Monoclonal/chemistry , Antineoplastic Agents, Immunological/chemistry , Chemistry, Pharmaceutical , Drug Development , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Molecular StructureABSTRACT
MLL1-WDR5 interaction is essential for the formation of MLL core complex and its H3K4 methyltransferase activity. Disrupting MLL1-WDR5 interaction has been proposed as a potential therapeutic approach in the treatment of leukemia. A "toolkit" of well-characterized chemical probe will allow exploring animal studies. Based on a specific MLL1-WDR5 PPI inhibitor (DDO-2117), which was previously reported by our group, we conducted a bioisosterism approach by click chemistry to discover novel phenyltriazole scaffold MLL1-WDR5 interaction blockers. Here, our efforts resulted in the best inhibitor 24 (DDO-2093) with high binding affinity (Kd = 11.6 nM) and with improved drug-like properties. Both in vitro and in vivo assays revealed 24 could efficiently block the MLL1-WDR5 interaction. Furthermore, 24 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. We propose 24 as a chemical probe that is suitable for in vivo pharmacodynamic and biological studies of MLL1-WDR5 interaction.
