Multi-Pole Approach to Structural Science

May 10 - 13, 2015

Structure-based development of menin-MLL inhibitors for cancer therapy.
Jolanta Grembecka, Dmitry Borkin, Hongzhi Miao, Jonathan Pollock, Katarzyna Kempinska, Trupta Purohit, Tomasz Cierpicki

Menin is a protein that directly interacts with the Mixed Lineage Leukemia 1 (MLL1) and MLL2 histone methyltransferases, and is required for their recruitment to the target genes. Menin also binds to MLL fusion proteins and this protein-protein interaction is required for development of acute leukemias with translocations of the MLL gene. Accumulating evidences suggest that menin complexes with MLL1 or MLL2 play a role in development of solid tumors. Therefore, small molecule inhibitors of the menin-MLL interaction might result in new therapeutics for leukemias and/or solid tumors.
By applying the high throughput screening followed by extensive medicinal chemistry we developed very potent small molecules that specifically bind to menin with low nanomolar affinities and inhibit the menin-MLL interaction in vitro and in human cells. Crystallography studies demonstrate that these compounds bind to the MLL binding site on menin and closely mimic the key MLL interactions with menin. Using structure-based design, we optimized both potency and drug-like properties of the thienopyrimidine class of the menin-MLL inhibitors, including pharmacokinetic profile, making them suitable for in vivo studies. These compounds demonstrate strong effect and specific mechanism of action in MLL leukemia cells, including inhibition of cell proliferation, induced differentiation and downregulation of MLL fusion protein target genes. More importantly, the menin-MLL inhibitors we developed block progression of acute leukemia in vivo in mice models of MLL leukemia, validating their therapeutic potential. Currently, broader applications of these compounds in various cancers are being explored. Our work provides another example of successful targeting of protein-protein interactions with small molecules for therapeutic applications.