11 research outputs found
Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo
Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification
Recommended from our members
Comparison of bead array and glass nanoreactor multi-analyte platforms for the evaluation of CNS and peripheral inflammatory markers during HIV infection.
While human immunodeficiency virus (HIV) infection has become a treatable disease with the development of combination antiretroviral therapy (cART), chronic inflammation that affects the central nervous system and other organs is still common. Reliable methods are needed to study HIV-associated inflammatory biomarkers. In this study involving both plasma and cerebrospinal fluid (CSF), we compared multiplex bead array (MBA) to a relatively new technology based on microfluidics and glass nanoreactor (GNR) technology for the measurement of three commonly studied markers from HIV-infected individuals. We found that results correlated between the two platforms for MCP-1 in both fluids as well as for plasma TNFα (all p < .005). However, results between the two platforms did not correlate for CSF TNFα or fractalkine from plasma or CSF. A statistically significant decrease in CSF TNFα over time (p < .0001) was only detectable with the MBA platform, and TNFα on the MBA was the only CSF biomarker to correlate with CSF HIV RNA (rho = 0.71, p < .0001). Meanwhile, the GNR platform was superior in terms of intra-assay fractalkine (FKN) variability and the detection of a significant FKN decrease over time. Additionally, the only significant correlation between blood biomarkers and plasma HIV RNA was with FKN on the GNR platform (rho = 0.38, p = .015). Given the variability in results between platforms, more research is needed on methods to quantitate HIV-associated inflammation
Recommended from our members
Comparison of bead array and glass nanoreactor multi-analyte platforms for the evaluation of CNS and peripheral inflammatory markers during HIV infection.
While human immunodeficiency virus (HIV) infection has become a treatable disease with the development of combination antiretroviral therapy (cART), chronic inflammation that affects the central nervous system and other organs is still common. Reliable methods are needed to study HIV-associated inflammatory biomarkers. In this study involving both plasma and cerebrospinal fluid (CSF), we compared multiplex bead array (MBA) to a relatively new technology based on microfluidics and glass nanoreactor (GNR) technology for the measurement of three commonly studied markers from HIV-infected individuals. We found that results correlated between the two platforms for MCP-1 in both fluids as well as for plasma TNFα (all p < .005). However, results between the two platforms did not correlate for CSF TNFα or fractalkine from plasma or CSF. A statistically significant decrease in CSF TNFα over time (p < .0001) was only detectable with the MBA platform, and TNFα on the MBA was the only CSF biomarker to correlate with CSF HIV RNA (rho = 0.71, p < .0001). Meanwhile, the GNR platform was superior in terms of intra-assay fractalkine (FKN) variability and the detection of a significant FKN decrease over time. Additionally, the only significant correlation between blood biomarkers and plasma HIV RNA was with FKN on the GNR platform (rho = 0.38, p = .015). Given the variability in results between platforms, more research is needed on methods to quantitate HIV-associated inflammation
Recommended from our members
Comparison of bead array and glass nanoreactor multi-analyte platforms for the evaluation of CNS and peripheral inflammatory markers during HIV infection.
While human immunodeficiency virus (HIV) infection has become a treatable disease with the development of combination antiretroviral therapy (cART), chronic inflammation that affects the central nervous system and other organs is still common. Reliable methods are needed to study HIV-associated inflammatory biomarkers. In this study involving both plasma and cerebrospinal fluid (CSF), we compared multiplex bead array (MBA) to a relatively new technology based on microfluidics and glass nanoreactor (GNR) technology for the measurement of three commonly studied markers from HIV-infected individuals. We found that results correlated between the two platforms for MCP-1 in both fluids as well as for plasma TNFα (all p < .005). However, results between the two platforms did not correlate for CSF TNFα or fractalkine from plasma or CSF. A statistically significant decrease in CSF TNFα over time (p < .0001) was only detectable with the MBA platform, and TNFα on the MBA was the only CSF biomarker to correlate with CSF HIV RNA (rho = 0.71, p < .0001). Meanwhile, the GNR platform was superior in terms of intra-assay fractalkine (FKN) variability and the detection of a significant FKN decrease over time. Additionally, the only significant correlation between blood biomarkers and plasma HIV RNA was with FKN on the GNR platform (rho = 0.38, p = .015). Given the variability in results between platforms, more research is needed on methods to quantitate HIV-associated inflammation
Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction
Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the ProteinProtein Interaction between Menin and Mixed Lineage Leukemia (MLL)
Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein–Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)
Development
of potent small molecule inhibitors of protein–protein
interactions with optimized druglike properties represents a challenging
task in lead optimization process. Here, we report synthesis and structure-based
optimization of new thienopyrimidine class of compounds, which block
the protein–protein interaction between menin and MLL fusion
proteins that plays an important role in acute leukemias with <i>MLL</i> translocations. We performed simultaneous optimization
of both activity and druglike properties through systematic exploration
of substituents introduced to the indole ring of lead compound <b>1</b> (MI-136) to identify compounds suitable for in vivo studies
in mice. This work resulted in the identification of compound <b>27</b> (MI-538), which showed significantly increased activity,
selectivity, polarity, and pharmacokinetic profile over <b>1</b> and demonstrated a pronounced effect in a mouse model of MLL leukemia.
This study, which reports detailed structure–activity and structure–property
relationships for the menin–MLL inhibitors, demonstrates challenges
in optimizing inhibitors of protein–protein interactions for
potential therapeutic applications
Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction
The protein–protein interaction
between menin and mixed-lineage
leukemia 1 (MLL1) plays an important role in development of acute
leukemia with translocations of the <i>MLL1</i> gene and
in solid tumors. Here, we report the development of a new generation
of menin–MLL1 inhibitors identified by structure-based optimization
of the thienoÂpyrimidine class of compounds. This work resulted
in compound <b>28</b> (<b>MI-1481</b>), which showed very
potent inhibition of the menin–MLL1 interaction (IC<sub>50</sub> = 3.6 nM), representing the most potent reversible menin–MLL1
inhibitor reported to date. The crystal structure of the menin-<b>28</b> complex revealed a hydrogen bond with Glu366 and hydrophobic
interactions, which contributed to strong inhibitory activity of <b>28</b>. Compound <b>28</b> also demonstrates pronounced
activity in MLL leukemia cells and <i>in vivo</i> in MLL
leukemia models. Thus, <b>28</b> is a valuable menin–MLL1
inhibitor that can be used for potential therapeutic applications
and in further studies regarding the role of menin in cancer
Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction
The protein–protein interaction
between menin and mixed-lineage
leukemia 1 (MLL1) plays an important role in development of acute
leukemia with translocations of the <i>MLL1</i> gene and
in solid tumors. Here, we report the development of a new generation
of menin–MLL1 inhibitors identified by structure-based optimization
of the thienoÂpyrimidine class of compounds. This work resulted
in compound <b>28</b> (<b>MI-1481</b>), which showed very
potent inhibition of the menin–MLL1 interaction (IC<sub>50</sub> = 3.6 nM), representing the most potent reversible menin–MLL1
inhibitor reported to date. The crystal structure of the menin-<b>28</b> complex revealed a hydrogen bond with Glu366 and hydrophobic
interactions, which contributed to strong inhibitory activity of <b>28</b>. Compound <b>28</b> also demonstrates pronounced
activity in MLL leukemia cells and <i>in vivo</i> in MLL
leukemia models. Thus, <b>28</b> is a valuable menin–MLL1
inhibitor that can be used for potential therapeutic applications
and in further studies regarding the role of menin in cancer