A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia

Abstract

Targeting protein‐protein interactions (PPIs) with small‐molecule inhibitors has become a hotbed of modern drug development. In this review, we describe a new class of PPI inhibitors that block menin from binding to MLL proteins. Menin is encoded by the MEN1 tumor suppressor, but acts as an essential cofactor for MLL/KMT2A‐rearranged leukemias. The most promising menin‐MLL inhibitors belong to the thienopyrimidine class and have recently entered phase I/II clinical trials for treating acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations. As single agents, thienopyrimidine compounds eradicate leukemia in a xenograft models of primary leukemic cells belonging to the MLL‐rearranged or NPM1‐mutant subtypes. These compounds are well tolerated with few or no side effects, which is remarkable given the tumor‐suppressor function of menin. The menin‐MLL inhibitors highlight how leukemia patients could benefit from a targeted epigenetic therapy with novel PPI inhibitors obtained by directed chemical evolution.

Multi-omics analyses of MEN1 missense mutations identify disruption of menin–MLL and menin–JunD interactions as critical requirements for molecular pathogenicity

“…The observation that menin is a critical cofactor for the subset of leukemias driven by chromosomal translocations involving MLL1/KMT2A motivated the development of menin-MLL inhibitors, which all target the MLL1-binding pocket of menin [11][12][13]. Several menin-MLL inhibitors display potent anti-leukemic activities in preclinical mouse models for MLL-rearranged and NPM1 mutant acute leukemias [14][15][16][17].…”

Recent Progress of Small Molecule Menin–MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia

“…Studies have shown that 8 out of 79 known MLL partner proteins (AF4, AF9, ENL, AF10, AF17, ELL, AF5q31, and LAF4) are involved in the transcriptional elongation process. According to the reports, these 8 fusion partners are expressed alone or in combination in 81% of 2345 patients with AL − (Figure ). Thus, the majority of MLL is caused by a loss of the correct transcriptional regulation.…”

“…The up-regulated expression level of the HOX or MEIS1 gene leads to the malignant proliferation of hematopoietic stem cells and the stagnation of differentiation. This results in the loss of hematopoietic capacity and the ultimate manifestation of acute leukemia . A rational hypothesis predicts that disrupting the interaction between menin and the MLL protein will downregulate the expression of the HOX or MEIS1 genes, restrict the proliferation ability of leukemia stem cells and restart differentiation of the stem cells to obtain hematopoietic capacity. , The prevalent mechanism of action is depicted in Figure .…”

Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

“…The observation that menin is a critical cofactor for the subset of leukemias driven by chromosomal translocations involving MLL1/KMT2A motivated the development of menin-MLL inhibitors, which all target the MLL1-binding pocket of menin (Grembecka et al , 2012; Ozyerli-Goknar et al , 2021; Yokoyama et al , 2005). Several menin-MLL inhibitors display potent anti-leukemic activities in preclinical mouse models for MLL-rearranged and NPM1 mutant acute leukemias (Dzama et al , 2020; Klossowski et al , 2020; Krivtsov et al , 2019; Uckelmann et al , 2020).…”