Publications by authors named "Hacer Karatas"

18 Publications

  • Page 1 of 1

A protein tertiary structure mimetic modulator of the Hippo signalling pathway.

Nat Commun 2020 10 27;11(1):5425. Epub 2020 Oct 27.

Max Planck Institute for Molecular Physiology, Dortmund, Germany.

Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein-protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.
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http://dx.doi.org/10.1038/s41467-020-19224-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591920PMC
October 2020

Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket.

J Med Chem 2020 10 1;63(20):11972-11989. Epub 2020 Oct 1.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany.

Transcriptional enhanced associate domain (TEAD) transcription factors together with coactivators and corepressors modulate the expression of genes that regulate fundamental processes, such as organogenesis and cell growth, and elevated TEAD activity is associated with tumorigenesis. Hence, novel modulators of TEAD and methods for their identification are in high demand. We describe the development of a new "thiol conjugation assay" for identification of novel small molecules that bind to the TEAD central pocket. The assay monitors prevention of covalent binding of a fluorescence turn-on probe to a cysteine in the central pocket by small molecules. Screening of a collection of compounds revealed kojic acid analogues as TEAD inhibitors, which covalently target the cysteine in the central pocket, block the interaction with coactivator yes-associated protein with nanomolar apparent IC values, and reduce TEAD target gene expression. This methodology promises to enable new medicinal chemistry programs aimed at the modulation of TEAD activity.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586386PMC
October 2020

TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics.

Angew Chem Int Ed Engl 2020 11 15;59(46):20338-20342. Epub 2020 Jul 15.

TU Dortmund University, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany.

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or "hot spot", regions of protein-protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide "hexT", encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
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http://dx.doi.org/10.1002/anie.202006280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689693PMC
November 2020

Identification of Quinolinols as Activators of TEAD-Dependent Transcription.

ACS Chem Biol 2019 12 2;14(12):2909-2921. Epub 2019 Dec 2.

Department of Multi-Modal Molecular (M3) Biology , Institute of Molecular and Cell Biology , 61 Biopolis Drive , 138673 Singapore.

The transcriptional co-regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are the vertebrate downstream effectors of the Hippo signaling pathway that controls various physiological and pathological processes. YAP and TAZ pair with the TEAD (TEA domain) family of transcription factors to initiate transcription. We previously identified a tractable pocket in TEADs, which has been physiologically shown to bind palmitate. Herein, a TEAD-palmitate interaction screen was developed to select small molecules occupying the palmitate-binding pocket (PBP) of TEADs. We show that quinolinols were TEAD-binding compounds that augment YAP/TAZ-TEAD activity, which was verified using TEAD reporter assay, RT-qPCR, and RNA-Seq analyses. Structure-activity relationship investigations uncovered the quinolinol substituents that are necessary for TEAD activation. We reveal a novel mechanism where quinolinols stabilize YAP/TAZ protein levels by occupying the PBP. The enhancement of YAP activity by quinolinols accelerates the wound closure in a mouse wound-healing model. Although small molecules that occupy the PBP have been shown to inhibit YAP/TAZ-TEAD activity, leveraging PBP to activate TEADs is a novel approach.
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http://dx.doi.org/10.1021/acschembio.9b00786DOI Listing
December 2019

Real-Time Imaging and Quantification of Peptide Uptake and .

ACS Chem Biol 2019 10 24;14(10):2197-2205. Epub 2019 Sep 24.

Laboratory of Bioorganic Chemistry and Molecular Imaging, Institute of Chemical Sciences and Engineering (ISIC) , Swiss Federal Institute of Technology Lausanne (EPFL) , 1015 Lausanne , Switzerland.

Peptides constitute an important class of drugs for the treatment of multiple metabolic, oncological, and neurodegenerative diseases, and several hundred novel therapeutic peptides are currently in the preclinical and clinical stages of development. However, many leads fail to advance clinically because of poor cellular membrane and tissue permeability. Therefore, assessment of the ability of a peptide to cross cellular membranes is critical when developing novel peptide-based therapeutics. Current methods to assess peptide cellular permeability are limited by multiple factors, such as the need to introduce rather large modifications (e.g., fluorescent dyes) that require complex chemical reactions as well as an inability to provide kinetic information on the internalization of a compound or distinguish between internalized and membrane-bound compounds. In addition, many of these methods are based on end point assays and require multiple sample manipulation steps. Herein, we report a novel "Split Luciferin Peptide" (SLP) assay that enables the real-time noninvasive imaging and quantification of peptide uptake both and using a very sensitive bioluminescence readout. This method is based on a straightforward, stable chemical modification of the peptide of interest with a d-cysteine tag that preserves the overall peptidic character of the original molecule. This method can be easily adapted for screening peptide libraries and can thus become an important tool for preclinical peptide drug development.
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http://dx.doi.org/10.1021/acschembio.9b00439DOI Listing
October 2019

The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis.

Nat Chem Biol 2019 07 20;15(7):710-720. Epub 2019 Jun 20.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

Autophagy mediates the degradation of damaged proteins, organelles and pathogens, and plays a key role in health and disease. Thus, the identification of new mechanisms involved in the regulation of autophagy is of major interest. In particular, little is known about the role of lipids and lipid-binding proteins in the early steps of autophagosome biogenesis. Using target-agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a new class of autophagy inhibitor. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain-containing protein 1A (GRAMD1A, which had not previously been implicated in autophagy), and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a new biological function of GRAMD1A and a new role for cholesterol in autophagy.
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http://dx.doi.org/10.1038/s41589-019-0307-5DOI Listing
July 2019

Chemical suppression of specific C-C chemokine signaling pathways enhances cardiac reprogramming.

J Biol Chem 2019 06 25;294(23):9134-9146. Epub 2019 Apr 25.

From the Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109,

Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low fibroblast-cardiomyocyte conversion rates remain a major challenge in this reprogramming. To this end, here we conducted a chemical screen and identified four agents, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-β inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, which coordinately enhanced reprogramming efficiency. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we observed that the IMAP treatment increases iCM formation 6-fold. IMAP stimulated higher cardiac troponin T and α-actinin expression and increased sarcomere formation, coinciding with up-regulated expression of many cardiac genes and down-regulated fibroblast gene expression. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we also observed that the IMAP treatment repressed many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways. We therefore investigated the roles of C-C motif chemokine ligand 3 (CCL3), CCL6, and CCL17 in cardiac reprogramming and observed that they inhibited iCM formation, whereas inhibitors of C-C motif chemokine receptor 1 (CCR1), CCR4, and CCR5 had the opposite effect. These results indicated that the IMAP treatment directly suppresses specific C-C chemokine signaling pathways and thereby enhances cardiac reprogramming. In conclusion, a combination of four chemicals, named here IMAP, suppresses specific C-C chemokine signaling pathways and facilitates Mef2c/Gata4/Tbx5 (MGT)-induced cardiac reprogramming, providing a potential means for iCM formation in clinical applications.
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http://dx.doi.org/10.1074/jbc.RA118.006000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556576PMC
June 2019

Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction.

J Med Chem 2017 06 12;60(12):4818-4839. Epub 2017 Jun 12.

Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Comprehensive Cancer Center, ∥Department of Pathology, ⊥Howard Hughes Medical Institute, #Department of Biological Chemistry, ∇Department of Pharmaceutical Sciences, ○Department of Pharmacology, and ¶Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.

We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC value of 0.90 nM (K value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01796DOI Listing
June 2017

In Vivo Molecular Bioluminescence Imaging: New Tools and Applications.

Trends Biotechnol 2017 07 10;35(7):640-652. Epub 2017 May 10.

Optical Molecular imaging, Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.

in vivo bioluminescence imaging (BLi) is an optical molecular imaging technique used to visualize molecular and cellular processes in health and diseases and to follow the fate of cells with high sensitivity using luciferase-based gene reporters. The high sensitivity of this technique arises from efficient photon production, followed by the reaction between luciferase enzymes and luciferin substrates. Novel discoveries and developments of luciferase reporters, substrates, and gene-editing techniques, and emerging fields of applications, promise a new era of deeper and more sensitive molecular imaging.
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http://dx.doi.org/10.1016/j.tibtech.2017.03.012DOI Listing
July 2017

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts.

Cell Discov 2016 11;2:16036. Epub 2016 Oct 11.

Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan , Ann Arbor, MI, USA.

Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.
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http://dx.doi.org/10.1038/celldisc.2016.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113048PMC
October 2016

MLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program.

Cell Discov 2016 17;2:16008. Epub 2016 May 17.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.

Mixed lineage leukemia protein-1 (MLL1) has a critical role in human MLL1 rearranged leukemia (MLLr) and is a validated therapeutic target. However, its role in regulating global gene expression in MLLr cells, as well as its interplay with MLL1 fusion proteins remains unclear. Here we show that despite shared DNA-binding and cofactor interacting domains at the N terminus, MLL1 and MLL-AF9 are recruited to distinct chromatin regions and have divergent functions in regulating the leukemic transcription program. We demonstrate that MLL1, probably through C-terminal interaction with WDR5, is recruited to regulatory enhancers that are enriched for binding sites of E-twenty-six (ETS) family transcription factors, whereas MLL-AF9 binds to chromatin regions that have no H3K4me1 enrichment. Transcriptome-wide changes induced by different small molecule inhibitors also highlight the distinct functions of MLL1 and MLL-AF9. Taken together, our studies provide novel insights on how MLL1 and MLL fusion proteins contribute to leukemic gene expression, which have implications for developing effective therapies in the future.
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http://dx.doi.org/10.1038/celldisc.2016.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869169PMC
July 2016

MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency.

Cell Stem Cell 2016 Apr 17;18(4):481-94. Epub 2016 Mar 17.

Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

The interconversion between naive and primed pluripotent states is accompanied by drastic epigenetic rearrangements. However, it is unclear whether intrinsic epigenetic events can drive reprogramming to naive pluripotency or if distinct chromatin states are instead simply a reflection of discrete pluripotent states. Here, we show that blocking histone H3K4 methyltransferase MLL1 activity with the small-molecule inhibitor MM-401 reprograms mouse epiblast stem cells (EpiSCs) to naive pluripotency. This reversion is highly efficient and synchronized, with more than 50% of treated EpiSCs exhibiting features of naive embryonic stem cells (ESCs) within 3 days. Reverted ESCs reactivate the silenced X chromosome and contribute to embryos following blastocyst injection, generating germline-competent chimeras. Importantly, blocking MLL1 leads to global redistribution of H3K4me1 at enhancers and represses lineage determinant factors and EpiSC markers, which indirectly regulate ESC transcription circuitry. These findings show that discrete perturbation of H3K4 methylation is sufficient to drive reprogramming to naive pluripotency.
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http://dx.doi.org/10.1016/j.stem.2016.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826731PMC
April 2016

Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia.

Mol Cell 2014 Jan 2;53(2):247-61. Epub 2014 Jan 2.

Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Here we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research.
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http://dx.doi.org/10.1016/j.molcel.2013.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965208PMC
January 2014

Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction.

J Med Chem 2013 Feb 17;56(3):1113-23. Epub 2013 Jan 17.

Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.

Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin-MLL1 protein-protein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), 34, binds to menin with a K(i) value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound 34 is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound 34 serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin-MLL1 interaction.
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http://dx.doi.org/10.1021/jm3015298DOI Listing
February 2013

High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.

J Am Chem Soc 2013 Jan 27;135(2):669-82. Epub 2012 Dec 27.

Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.
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http://dx.doi.org/10.1021/ja306028qDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5180416PMC
January 2013

Synthesis and potent in vitro activity of novel 1H-benzimidazoles as anti-MRSA agents.

Chem Biol Drug Des 2012 Aug 30;80(2):237-44. Epub 2012 Apr 30.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey.

A new class of 1H-benzimidazolecarboxamidines was synthesized and evaluated for in vitro antibacterial and antifungal activities, including drug-resistant bacterial strains. The most potent compound (32) has the same ratio of anti-MRSA activity as Vancomycin (minimal inhibitory concentrations value 0.78 μg/mL). The mechanism of action for 1H-benzimidazolecarboxamidine appears to be different from existing antibacterial agents. These compounds have potential for development as a new class of potent anti-MRSA agent.
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http://dx.doi.org/10.1111/j.1747-0285.2012.01393.xDOI Listing
August 2012

Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction.

J Med Chem 2010 Jul;53(14):5179-85

Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

MLL1 is a histone 3 lysine 4 (H3K4) methyltransferase and a promising new cancer therapeutic target. The catalytic activity of MLL1 is regulated by the formation of a core complex consisting of MLL1, WDR5, RbBP5, and Ash2L. The interaction between WDR5 and MLL1 plays an essential role in regulation of the H3K4 methyltransferase activity of MLL1 and targeting this interaction using small molecules may represent an attractive therapeutic strategy. In this study, we have defined the essential elements in MLL1 required for its high-affinity binding to WDR5. Our data showed that the minimal elements crucial for high-affinity binding of MLL1 to WDR5 are -CO-ARA-NH- motif and two intramolecular hydrogen bonds that stabilize the conformation of this motif. Two 3-mer peptides, Ac-ARA-NH(2) and Ac-ART-NH(2), were designed based upon MLL1 and H3 sequences and achieved K(i) values of 120 and 20 nM to WDR5, respectively. Our study provides a concrete basis for the design of potent peptidomimetics and nonpeptidic compounds to inhibit MLL1 activity by targeting the MLL1 and WDR5 interaction.
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http://dx.doi.org/10.1021/jm100139bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289617PMC
July 2010

Synthesis and potent antimicrobial activity of some novel 4-(5, 6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzamides.

Arch Pharm (Weinheim) 2004 Oct;337(10):556-62

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey.

A series of 4-(5, 6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzamides were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermis (MRSE), Enterococcus faecalis, Escherichia coli and Candida albicans. Certain compounds inhibit bacterial growth with low MIC values (microg/mL). Among them, compounds 10 and 11 exhibited the greatest antibacterial activity with MIC values of 3.12 microg/mL against S. aureus, MRSA and MRSE.
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http://dx.doi.org/10.1002/ardp.200400884DOI Listing
October 2004