Summary Translocations involving the Mixed Lineage Leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the MEN1 gene. Here, we present the first small molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind to menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a smallmolecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K d ؍ IntroductionTranslocations of the MLL (mixed lineage leukemia) gene frequently occur in aggressive human acute myeloid and lymphoid leukemias in both children and adults. 1 Fusion of MLL with 1 of more than 60 different genes results in chimeric MLL fusion proteins that enhance proliferation and block hematopoietic differentiation, ultimately leading to acute leukemia. 2 Patients with leukemias harboring MLL translocations have very unfavorable prognoses and respond poorly to currently available treatments. 2,3 The relapse risk is very high using conventional chemotherapy and stem cell transplantation, 2 leading to an overall 5-year survival rate of only approximately 35%. 4 All MLL fusion proteins preserve an N-terminal MLL fragment approximately 1400 amino acids in length fused in-frame with the C-terminus of the fusion partner. 3,[5][6][7] Two regions in this fragment of MLL have been shown to be indispensable for leukemogenic transformation: the N-terminal region, which binds to menin 8 and to lens epithelium-derived growth factor (LEDGF), 9 and the conserved region encompassing the CXXC domain, which mediates binding to nonmethylated CpG DNA [10][11][12] and interacts with the polymerase associated factor complex (PAFc). 13,14 Targeting these interactions provides new opportunities for the development of new therapeutic agents for the MLL leukemias. 15 Menin is a tumor-suppressor protein encoded by the MEN1 (multiple endocrine neoplasia 1) gene. 16 Mutations of MEN1 are associated with tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. 17 Menin is also a highly specific binding partner for MLL and MLL fusion proteins and is required to regulate the expression of MLL target genes, including HOXA9 and MEIS1. 8 Loss of the ability to bind menin abolishes the oncogenic potential of MLL fusion proteins both in vitro and in vivo. 8 Disruption of the interaction between menin and MLL fusion proteins using genetic methods blocks the development of acute leukemia in mice, 8 indicating that menin functions as a critical oncogenic cofactor of MLL fusion proteins and is required for their leukemogenic activity. The menin-MLL interaction represents an attractive therapeutic target for the development of novel drugs for acut...
Promising anti-breast cancer agents derived from substituted quinolines were discovered. The quinolines were readily synthesized in large scale from a sequence of reactions starting from 4-acetamidoanisole. The Michael addition product was isolated as the reaction intermediate in the ring closing reaction of 4-amino-5-nitro-2-(3-trifluoromethylphenyloxy)anisole with methyl vinyl ketone leading to 6-methoxy-4-methyl-8-nitro-5-(3-trifluoromethylphenyloxy)quinoline (14). The amino function of 8-amino-6-methoxy-4-methyl-5-(3-trifluoromethylphenyloxy)quinoline, prepared from 14, was connected to various side chains via alkylation with N- (3-iodopropyl)phthalimide, Michael addition with acrylonitrile, and reductive amination with various heterocycle carboxaldehydes, such as imidazole-4-carboxaldehyde, thiophene-2-carboxaldehyde, and 2-furaldehyde. Effects of the substituted quinolines on cell viability of T47D breast cancer cells using trypan blue exclusion assay were examined. The results showed that the IC 50 value of 6-methoxy-8-[(2-furanylmethyl)amino]-4-methyl-5-(3-trifluoromethylphenyloxy)quinoline is 16 ± 3 nM, the lowest IC 50 out of all the quinolines tested. IC 50 values of three other quinolines are in the nanomolar range, a desirable range for pharmacological testing. Keywordssynthesis of substituted quinolines; anti-breast-cancer agents; T47D breast cancer cells Quinolines are known for their anti-malarial, 1-3 leishmanicidal, 4 antibacterial 5 and anticancer activities. 6-9 Recently, quinolines were examined in ATP-binding cassette drug transporter inhibition, 6 targeting tumor hypoxia, 7 modulation of multidrug resistance, 8 and tyrosine kinase inhibition. 9 Based on these literature results, we investigated substituted quinolines in search of novel anti-breast cancer compounds. After our initial anticancer screening, we focused on substituted quinolines with a skeletal structure derived from 8-amino-5-(aryloxy)-6-methoxy-4-methylquinoline, 1 by derivatizing its C8-amino side chain. We report † This manuscript is dedicated to Professor E. J. Corey on the occasion of his 80 th birthday. *Corresponding author. Tel.: 785-532-6699; fax: 785-532-6666; e-mail: duy@ksu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2009 June 1. We utilized a similar synthetic method leading to 5-(aryloxy)-4-methylprimaquine 1,10 by starting with 4-acetamidoanisole (8) via sequential C2 and C5 functionalizations followed by a ring closing reaction. Hence, 2-bromo-4-acetamino-5-nitro...
Small β‐amyloid (Aβ) 1–42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimer’s disease (AD). Methods to reduce the level of Aβ, prevent Aβ aggregation, and eliminate existing Aβ aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Aβ oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Aβ42 oligomer. Circular dichroism spectroscopy reveals monomeric Aβ42 peptide remains as a random coil/α‐helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Aβ42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed‐fluid cell study demonstrates that CP2 disaggregates Aβ42 oligomers and protofibrils. CP2 also blocks Aβ fibrillations using a protein quantification method. Treatment of 5× familial Alzheimer’s disease mice, a robust Aβ42‐producing animal model of AD, with a 2‐week course of CP2 resulted in 40% and 50% decreases in non‐fibrillar and fibrillar Aβ species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Aβ aggregation and disaggregating existing Aβ oligomers and protofibrils.
Cancer is caused in part by the disruption in cell homeostasis, affecting the ability to respond to extracellular signals, triggering some intracellular events that affect gap junctional intercellular communication (GJIC). Cancer cells have reduced or altered GJIC capacity. One feasible approach to reduce growth of cancer cells is to enhance/alter the GJIC. The capability of cells to communicate through the gap junction is negatively related to their growth activity. A computational docking study showed that a new class of substituted quinolines designated as PQs had a relatively high binding to gap junction protein, connexin 43. Thus, PQs were used in this study to assess their effect on human breast cancer cells. Scrape load/dye transfer and colony growth assays were performed to measure GJIC and determine the effect of the PQ compounds on colony formation in human normal mammary epithelial cells (HMEC) and breast cancer cells, respectively. PQs had a significant antitumor effect in human breast cancer cells compared with control without treatment or normal mammary epithelial cells. PQ1 (200 nM) showed a 30% increase in the GJIC in T47D cells; however, there was no effect of PQ treatment on GJIC in normal mammary epithelial cells. In addition to an increase in GJIC, 80-95% growth attenuation was observed by PQ1 in colony growth assay. Moreover, an increase in caspase 3 with PQ-treated cells was observed, suggesting a possible involvement in apoptosis. PQ1-treated animals showed a significant decrease in xenograft tumor growth of T47D cells in nude mice compared with control or tamoxifen-treated animals. The results show that PQ1 has a promising role in exerting antitumor activity in human breast cancer cells. Treatment with PQ1 in T47D cells caused an increase in GJIC activity and active caspase 3, and a decrease in colony growth and cell viability. Drug Dev Res 69 : 526-534,
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.