Challenges and Opportunities in Targeting the Menin–MLL Interaction

Abstract

Menin is an essential co-factor of oncogenic MLL fusion proteins and the menin-MLL interaction is critical for development of acute leukemia in vivo. Targeting the menin-MLL interaction with small molecules represents an attractive strategy to develop new anticancer agents. Recent developments, including determination of menin crystal structure and development of potent small molecule and peptidomimetic inhibitors, demonstrate feasibility of targeting the menin-MLL interaction. On the other hand, biochemical and structural studies revealed that MLL binds to menin in a complex bivalent mode engaging two MLL motifs, and therefore inhibition of this protein-protein interaction represents a challenge. This review summarizes most recent achievements in targeting the menin-MLL interaction as well as discusses potential benefits of blocking menin in cancer.

Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

“…Toxicity of this compound did not allow its use in cell growth assays. However, more specific and potent menin-MLL inhibitors have been developed (Cierpicki and Grembecka, 2014). Such compounds have been shown to suppress growth in AR expressing prostate cancer models (Malik et al, 2015).…”

Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

“…In addition, its architecture remains relatively rigid upon binding of MLL, thus making menin a druggable and yet challenging PPI interface for the development of small molecule inhibitors. Current inhibitors of the menin-MLL interaction 9 include peptidomimetics such as MCP-1 (1) 10 and two classes of small molecule inhibitors including the thienopyrimidines MI-2 (2) and MI-2-2 (3) 11,12 and hydroxymethylpiperidines ML227 (4) 13,14 (Fig. 1); the later class of which was discovered from an NIH Molecular Libraries Production Center Network (MLPCN) sponsored screen of the Molecular Libraries Small Molecule Repository (MLSMR) of 280 K compounds.…”

“…Menin is a ubiquitously expressed nuclear protein capable of binding directly to both wild type MLL1, MLL2, and MLL1 fusion protein complexes and is thought to function by targeting their recruitment to the target genes which includes the homeotic genes Hoxa9, Hoxc6, and Hoxc8. 8,9 Menin contains a large and well defined central cavity (human menin 5000 Å 3 ) that represents the MLL binding site. In addition, its architecture remains relatively rigid upon binding of MLL, thus making menin a druggable and yet challenging PPI interface for the development of small molecule inhibitors.…”

Design of a fluorescent ligand targeting the S-adenosylmethionine binding site of the histone methyltransferase MLL1

“…However, a wild-type allele of MLL1 is required for the transformative capacity of the oncogenic fusion proteins 16 , leading us and others to target the catalytic activity of wild-type MLL1 17, 18 . Significant progress has been made in both of these areas, including targeting the MLL-menin and MLL-WDR5 interactions 11-15, 17-19 . Recently OICR-9429, a WDR5 antagonist has been reported to dissociate the MLL1-WDR5-RbBP5 complex, selectively inhibit proliferation, and induce differentiation in p30-expressing human AML cells 20 .…”