Targeting the menin-MLL-LEDGF Interaction with Small Molecule Inhibitors.

Small molecule inhibitors;protein-protein interaction;Biological Chemistry;Science;Molecular & Cellular Pathology

Pollock, JonathanNikolovska-Coleska, Zaneta ;

University of Michigan

关键词: Small molecule inhibitors;    protein-protein interaction;    Biological Chemistry;    Science;    Molecular & Cellular Pathology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/135906/pollojon_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Mixed Lineage Leukemia 1 (MLL) is a large multi-domain protein (430 kDa) encoded by the MLL gene that catalyzes the methylation of histone H3 lysine 4 (H3K4).Chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene result in acute myeloid and lymphoblastic leukemias. MLL mediated leukemia is present in about 10% of adult acute leukemia and up to 70% of infant leukemias.Patients with MLL leukemia do not respond well to conventional treatment methods; therefore, have very poor prognosis with only about a 35% overall 5-year survival rate and high risk of relapse. This demonstrates the urgent need for novel targeted therapeutics to treat these leukemias. Chromosomal translocation of the MLL gene with one of over 60 partner genes generates an oncogenic chimeric fusion protein. MLL fusion proteins lead to enhanced cell proliferation, up-regulation of Hoxa9 and Meis1 genes and block hematopoietic differentiation, ultimately leading to acute leukemia. The oncogenic function of MLL fusion proteins is reliant on the interaction with menin and with Lens Epithelium Derived Growth Factor (LEDGF).Menin functions as a scaffolding protein and interacts with wild type (WT) MLL or MLL fusion proteins which are localized to target genes through association with LEDGF. Formation of the menin-MLL-LEDGF ternary complex is critical for MLL associated gene regulation and leukemogenic transformation.Therefore, inhibition of the menin-MLL interaction should abrogate the development and progression of MLL leukemia.Our laboratory was the first to report small molecule inhibitors of the menin-MLL interaction.We have identified two classes of reversible menin-MLL inhibitors and rationally designed a new class of covalent menin-MLL inhibitors. Using high resolution crystal structures of menin in complex with inhibitors we applied structure-based design to further optimize inhibitors of the menin-MLL interaction. We performed extensive characterization and optimization of potency, solubility and pharmacokinetic properties of these compounds. These efforts led to the development of compounds suitable for in vivo analysis and demonstrated significant survival benefit in murine models of MLL leukemias. Overall, we have demonstrated that menin-MLL inhibitors may offer a novel therapeutic strategy for MLL leukemia patients and have developed a promising lead scaffold for clinical optimization.