Menin-MLL protein-protein interaction inhibitors: a patent review (2021-present)

Acute leukemia harboring rearrangement of the Mixed lineage leukemia (MLL) and/or mutation of the nucleophosmin is a type of poorly prognostic and highly malignant leukemia which is extremely difficult to treat. Blocking the protein-protein interaction between Menin and MLL is a strategic approach for treating leukemias, as a new direction for drug discovery. Many biotech and pharmaceutical companies made great efforts to this drug development field, and a large number of small molecular Menin-MLL PPI inhibitors were reported during the recent three years.

This review is to mainly summarize the Menin-MLL PPI inhibitors reported in the recent three years' patents.

Although the past 12 years have witnessed the progress of the Menin-MLL PPI inhibitors in the treatment of acute leukemia, especially for leukemia harboring rearranged KMT2A and/or mutated NPM1, recent studies showed Menin-MLL PPI inhibitors suffered from new issues such as toxicity, acquired resistance, and homogenization. Therefore, new drug discovery strategies should be considered in advance. The expert opinion was proposed from several aspects, such as developing diverse chemical structures, discovering covalent inhibitors, designing small molecular PROTACs, and targeting the amino acids mutations for next-generation inhibitors.