Menin-MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers

Abstract

Encoded by the MEN1 gene, menin protein is a fusion protein that is essential for the oncogenic transformation of mixed-lineage leukemia (MLL) and leads to acute leukemia (AL). Therefore, accumulating evidence has demonstrated that inhibition of the high-affinity relationship between menin and mixed-lineage leukemia 1 (MLL1 and KMT2A) is an effective treatment for MLL-rearranged (MLL-r) leukemia in vitro and in vivo. Meanwhile, recent studies found that menin-MLL1 interaction inhibitors exhibited a firm tumor suppressive ability in specific cancer cells, such as prostate cancer, breast cancer, liver cancer, and lung cancer. Overall, it seems to serve as a novel therapeutic means for cancers. Herein, we review the recent progress in exploring the inhibitors of small molecule menin-MLL1 interactions. The molecular mechanisms of these inhibitors' functions and their application prospects in the treatment of AL and cancers are explored.

Keywords: cancer; leukemia; menin-MLL1 complex; molecule inhibitor; therapeutics strategies.

Figure 1

Molecular mechanisms of Hydroxymethyl and aminomethyl piperidine inhibitors in treating leukemia and cancers. Four inhibitors, M-525, M-808, M-89, and M-1121, block the interaction between menin and MLL-AF4, MLL-AF9 fusion protein to reduce the expression of MEIS1 and HOXA9 genes and inhibit the proliferation of MLL-r leukemia cells.

Figure 2

Molecular mechanisms of thiophenpyrimidine inhibitors in treating leukemia and cancers. (A) The interaction between menin and MLL-AF4, MLL-AF9, and MLL-ENL fusion proteins is blocked by MI-2 and MI-3 inhibitors to reduce the transcription of HOXA9 and MEIS1 genes, which is accompanied by the reduction of H3K4 trimethylation and H3K79 dimethylation and inhibit the MLL-r leukemia cell growth. (B) MI-2 blocks the menin−MLL interaction combined with β-catenin inhibitor ICG-001 to reduce the expression of H3K4me3 in the Wnt signaling pathway target genes Axin2, Id2, Tcf7l2, thereby inhibiting the proliferation of salivate gland and head and neck tumor cells. (C) MI-3 blocks the menin−MLL interaction and decreases the Rasgrf1 expression. The GTP binding activity of Kras is inhibited, thus limiting the proliferation of Kras mutant lung cancer cells. (D) MI-136 blocks the menin−MLL interaction to reduce the transcription of AR target genes TMPRSS2 and FKBP5, thus inhibiting the AR-dependent cell growth in prostate cancer. (E) MI-136 blocks the menin−MLL interaction to restrict the transcription of HIF signaling pathway target genes Nos2, Nos3, Cav1, thereby inhibiting the proliferation of endometrial cancer cells. (F) The interaction between menin and MLL-AF4, MLL-AF9 fusion proteins is blocked by MI-148, MI-538, MI-503, and MI-463, thus reducing the expression of HOXA9 and MEIS1 genes and inhibiting the proliferation of MLL-r leukemia cells, respectively. The increased expression of CD11b and MNDA, markers of cell differentiation, promoted the differentiation of leukemia cells into normal cells. (G) MI-136 and menin−MLL complex members MLL, MED12, GATA3 synergically inhibited the promoting effect of menin on OXPHOS gene expression. For glycolysis, MI-503 blocks the menin−MLL interaction to reduce the transcriptional activity of glycolysis genes. (H) MI-503 blocks the menin−JunD interaction and decreases the expression of menin and JunD. It also inhibits the transcription of JunD target gene c-MYC and the proliferation of AR-independent cells in prostate cancer. (I) MI-503 inhibits the interaction between menin and MLL1 to reduce the level of H3K4me3 on the promoter of the PEG10 gene and limits hepatocellular carcinoma cell growth. (J) MI-503 and VTP-50469 inhibitors restrict the menin-MLL1 interaction to reduce the level of H3K4me3 on the promoter of PHGDH, PSAT1, and PSPH genes related to the serine biosynthesis pathway (SSP), subsequently inhibiting the growth of Ewing′s sarcoma cancer cells. (K) VTP-50469 blocks the interaction between menin and MLL-AF4, MLL-AF9 fusion proteins to reduce the transcription of the MEIS1 gene to target the expression of FLT3. Thus, it intensifies the depletion of phosphorylated FLT3 mediated by FLT3 inhibitor and produces synergistic antileukemia impact on NPM1mut or MLL-r leukemia. (L) KO-539 blocks the interaction between menin and MLL-AF4 and MLL-AF9 fusion proteins to reduce the expression of HOXA9 and MEIS1 genes. Meanwhile, the ubiquitin-proteasome pathway leads to the degradation of menin protein, which has a synergistic antileukemia impact on NPM1mut or MLL-r leukemia. (M) MI-3454 blocks the interaction between menin and MLL-AF4, MLL-AF9, and MLL-ENL fusion proteins to reduce the expression of HOXA9, MEIS1, and FLT3 genes, which has a synergistic antileukemia impact on NPM1-mut or MLL-r leukemia.