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Chromosomal translocations involving the mixed-lineage leukemia (MLL, KMT2A, MLL1) genes result in the production of MLL fusion proteins, which cause abnormal transcriptional regulation leading to acute leukemia (AL). Menin (MEN1) protein is essential for MLL to regulate the expression of related target genes. High-affinity interactions between the amino terminus of MLL proteins and Menin proteins are required to mediate the oncogenic transformation of MLL fusion proteins. Therefore, inhibition of Menin and MLL interaction is a potential therapeutic strategy for MLL rearrangement (MLL-r) leukemia and can provide a new choice for treatment of other diseases. Therefore, researchers have made great efforts to explore small-molecule Menin-MLL interaction inhibitors. This review is to provide an overview of the patented Menin-MLL protein-protein interaction inhibitors from 2014 to 2021. Menin-MLL interaction inhibitors have therapeutic potential in the treatment of acute leukemia, such as AML and ALL. SNDX-5613 and KO-539 have been granted orphan drug designation by the FDA for treatment of refractory/relapsed leukemia and AML, respectively. In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.

Menin-MLL protein-protein interaction inhibitors: a patent review (2014–2021)