Cierpicki Tomasz, Grembecka Jolanta
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Future Med Chem. 2014 Mar;6(4):447-62. doi: 10.4155/fmc.13.214.
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 the 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 the most recent achievements in targeting the menin-MLL interaction as well as discusses potential benefits of blocking menin in cancer.
Menin是致癌性MLL融合蛋白的必需辅助因子，且Menin与MLL的相互作用对于体内急性白血病的发展至关重要。用小分子靶向Menin与MLL的相互作用是开发新型抗癌药物的一个有吸引力的策略。最近的进展，包括Menin晶体结构的确定以及强效小分子和拟肽抑制剂的开发，证明了靶向Menin与MLL相互作用的可行性。另一方面，生化和结构研究表明，MLL以一种涉及两个MLL基序的复杂二价模式与Menin结合，因此抑制这种蛋白质-蛋白质相互作用是一项挑战。本综述总结了靶向Menin与MLL相互作用的最新成果，并讨论了在癌症中阻断Menin的潜在益处。
