Abstract
Inhibiting the interaction of menin with the histone methyltransferase MLL1 (KMT2A) has recently emerged as a novel therapeutic strategy. Beneficial therapeutic effects have been postulated in leukemia, prostate, breast, liver and in synovial sarcoma models. In those indications, MLL1 recruitment by menin was described to critically regulate the expression of disease associated genes. However, most findings so far rely on single study reports. Here we independently evaluated the pathogenic functions of the menin-MLL interaction in a large set of different cancer models with a potent and selective probe inhibitor BAY-155. We characterized the inhibition of the menin-MLL interaction for anti-proliferation, gene transcription effects, and for efficacy in several in vivo xenografted tumor models. We found a specific therapeutic activity of BAY-155 primarily in AML/ALL models. In solid tumors, we observed anti-proliferative effects of BAY-155 in a surprisingly limited fraction of cell line models. These findings were further validated in vivo. Overall, our study using a novel, highly selective and potent inhibitor, shows that the menin-MLL interaction is not essential for the survival of most solid cancer models. We can confirm that disrupting the menin-MLL complex has a selective therapeutic benefit in MLL-fused leukemia. In solid cancers, effects are restricted to single models and more limited than previously claimed.
Highlights
Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene.Mutations of menin cause a hereditary autosomal dominant tumor syndrome (MEN1 syndrome) leading to tumorigenesis in multiple endocrine organs [1,2]
In search for an optimal chemical probe, we aimed for novel menin inhibitors with potencies and DMPK properties superior to MI-503, which is often used in other studies as the menin-MLL
BAY-155 appeared as the most promising menin inhibitor compared to several other potent spirocyclic amines identified during our optimisation studies
Summary
Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. Mutations of menin cause a hereditary autosomal dominant tumor syndrome (MEN1 syndrome) leading to tumorigenesis in multiple endocrine organs [1,2]. Menin shows no homology to other known proteins and its precise function is still poorly understood. Significant efforts have been made to identify interacting proteins which might allow for a better understanding of the physiological and tumor-specific functions of menin [2,3,4]. Menin associates with different proteins that activate or repress the transcription of genes involved in multiple cellular processes. Interaction of menin with the JUN family transcription factor JunD has been demonstrated to Cancers 2020, 12, 201; doi:10.3390/cancers12010201 www.mdpi.com/journal/cancers
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