AU2019395201A1 — Cycloalkane-1,3-diamine derivative

USPTO Abstract

Chromosomal translocation of the MLL (Mixed-Lineage Leukemia) gene is observed for infant leukemia and some poor-prognosis leukemia cases. MLL, as a result of chromosomal translocation, fuses with 70 or more various translocation partner genes at the amino terminus thereof to express an MLL fusion protein. Wild-type MLL constructs a transfer regulation complex that modifies the chromatin structure, and specifically methylates lysine at position 4 of histone H3, playing a very important role in the transcription regulation of gene clusters (for example, HOX gene cluster, etc.) involved in hematogenesis and neogenesis. Meanwhile, the MLL fusion protein, the expression thereof being induced by chromosomal translocation, has lost the histone methylation enzyme activity, but activates gene clusters (for example, HOX and MEIS1 genes, etc.) involved in the cell differentiation control permanently. As a result, abnormal cell proliferation and inhibition of differentiation induction of hematopoietic cells are triggered, which leads to onset of leukemia. Leukemia involving a mutant MLL gene has poor prognosis, and the standard treatment used for leukemia treatment today does not demonstrate full effectiveness. For this reason, the development of new regimen of therapy is in strong demand. Menin is a tumor-suppressor protein identified as a causal factor of multiple endocrine neoplasia type 1 (MEN1), which is one of autosomal dominant inherited neoplasia syndromes, characterized by the tumor formation in multiple endocrine organs. Menin is a ubiquitously expressed nucleoprotein, interacts with a wide variety of proteins, and is involved in various cellular processes. It is considered that the biological functions of menin can be tumor-suppressing or tumor-promoting, depending on the cell context. Menin interacts with the amido terminus of MLL1, and functions as carcinogenic cofactor that increases the transcription of gene clusters such as HOX and MEIS1. It is known that the interaction between menin and an MLL fusion protein is essential for abnormal activation of a series of gene clusters and onset of leukemia caused by the MLL fusion protein (non-patent documents 1 and 2). Thus, it is expected that inhibition of the interaction between menin and an MLL fusion protein contributes to the treatment and/or prevention of leukemia involving MLL gene chromosomal translocation and other leukemia/hematological cancer accompanied by constant expression of HOX and MEIS1 genes. Accordingly, for example, the creation of a drug that inhibits the interaction between menin and an MLL fusion protein is of great significance from the perspective of providing a novel option for cancer treatment. A plurality of compounds are already known to exhibit inhibitory activity against the interaction between menin and an MLL protein (patent documents 1 to 4, non-patent documents 3 to 5).