Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

Senter, Timothy J.; Gogliotti, Rocco D.; Han, Changho; Locuson, Charles W.; Morrison, Ryan D.; Daniels, J. Scott; Cierpicki, Tomasz; Grembecka, Jolanta; Lindsley, Craig W.; Stauffer, Shaun R.

doi:10.1016/j.bmcl.2015.04.026

Cited by 11 publications

(14 citation statements)

References 20 publications

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“…Therefore, MLL1 may prove to be an effective therapeutic target for infectious diseases that exhibit severe immunopathology as a major driver of morbidity and mortality. With the first generation of MLL1 inhibitors now becoming available(31), it may be beneficial to consider their future use for restricting pathogen-induced immunopathology, such as in severe sepsis responses, viral infections (e.g. influenza) or other pathogen-mediated inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages

Carson

Cavassani

Soares

et al. 2017

The Journal of Immunology

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Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications such as histone methylation regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin modifying enzymes. The histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function has been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-κB. We therefore sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre+/− MLL1fx/fx) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1 knockout macrophages indicated numerous genes involved with inflammatory responses whose expression was altered in response to Toll-like receptor ligands or proinflammatory cytokines, including signal transducer and activator of transcription 4 (STAT4). STAT4-dependent cytokines such as Type I Interferons were able to drive MLL1 expression in macrophages, and MLL1 knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions.

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Section: Discussionmentioning

confidence: 99%

The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages

Carson

Cavassani

Soares

et al. 2017

The Journal of Immunology

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“…Among them are: The macrocyclic peptidomimetic MCP-1 [ 52 ], The thienopyrimidine MI-2-2 [ 53 ] and its derivatives MI-463/503 [ 54 ] with MI-2-2 being poorly stable and could not be used in vivo rather than MI-463 and MI-503 (a derivative of MI-463 by the addition of a single methylpyrazole) which both interact with menin at nanomolar range, are more metabolically stable and exert strong cellular and in vivo activity, MI-503 being the most efficient one with deeper contacts with the menin pocket [ 54 ], The hydroxymethylpiperidines ML227, MIV-6 and cyclopentylphenylpiperidine derivative M-525 [ 55 , 56 , 57 ] that mimic the interacting MLL peptide and may be used together with DOT1L inhibitors to restore differentiation in MLL-rearranged leukemias [ 58 ]. ML227 presents poor metabolic stability as well as off target activities that limited its developement and an IC 50 for interation to menin of 390 nM [ 56 ]. MIV-6 differs from ML227 by an amine group that substitute to the hydroxyl group of ML227 and is more stable but with similar range of IC 50 for menin (185 nM) whereas M-525 is much more efficient on menin interaction with IC 50 of 3.3 nM and is 30-fold more potent in cellular activities with a hiogh specificity on mixed lineage leukemia cell models such as MV4;11 [ 57 ].…”

Section: Targeting Transcription Factor At the Expression Levelmentioning

confidence: 99%

Section: Targeting Transcription Factor At the Expression Levelmentioning

confidence: 99%

“…The hydroxymethylpiperidines ML227, MIV-6 and cyclopentylphenylpiperidine derivative M-525 [ 55 , 56 , 57 ] that mimic the interacting MLL peptide and may be used together with DOT1L inhibitors to restore differentiation in MLL-rearranged leukemias [ 58 ]. ML227 presents poor metabolic stability as well as off target activities that limited its developement and an IC 50 for interation to menin of 390 nM [ 56 ]. MIV-6 differs from ML227 by an amine group that substitute to the hydroxyl group of ML227 and is more stable but with similar range of IC 50 for menin (185 nM) whereas M-525 is much more efficient on menin interaction with IC 50 of 3.3 nM and is 30-fold more potent in cellular activities with a hiogh specificity on mixed lineage leukemia cell models such as MV4;11 [ 57 ].…”

Section: Targeting Transcription Factor At the Expression Levelmentioning

confidence: 99%

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Targeting Transcription Factors for Cancer Treatment

et al. 2018

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Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

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“…In animal models, KO-539 was given by the oral route and evidenced weak toxicity in mice and potent leukemic cells differentiation (CD11b-expressing cells in bone marrow of treated mice) and anti-leukemic effects (reduced splenomegaly and increased global survival) in both the MV4-11 MPAL model and patient-derived xenografts from the NPM1c+/FLT3-mut AML subtype [149]. Among other menin inhibitors are the hydroxyl-methyl-piperidines ML227, MIV-6, and their cyclopentyl-phenyl-piperidine derivative M-525, which all mimic the MLL-interacting peptide [150,151,152]. Such compounds were evaluated in combination with DOT1L inhibitors to restore differentiation in MPAL cell models [153].…”

Section: Indirect Targeting Of Hoxa9 At the Expression Levelmentioning

confidence: 99%

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

Lambert

Alioui

Jambon

et al. 2019

Cancers

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HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an “undruggable” target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.

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Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

Cited by 11 publications

References 20 publications

The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages

The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages

Targeting Transcription Factors for Cancer Treatment

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

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