FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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Identification of a Novel Benzimidazole Pyrazolone Scaffold That Inhibits KDM4 Lysine Demethylases and Reduces Proliferation of Prostate Cancer Cells
Carter(*), D. M., Specker, E., Przygodda, J., Neuenschwander, M., von Kries, J. P., Heinemann(*), U., Nazare, M.; Gohlke(*), U.
SLAS discovery, 22:801-812

Tags: Screening Unit (von Kries), Medicinal Chemistry (Nazare)

Abstract: Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment. To address this possibility, we screened the ChemBioNet small molecule library for inhibitors of the human KDM4E isoform and identified several compounds with IC50 values in the low micromolar range. Two hits, validated as active by an orthogonal enzyme-linked immunosorbent assay, displayed moderate selectivity toward the KDM4 subfamily and exhibited antiproliferative effects in cellular models of PCa. These compounds were further characterized by their ability to maintain the transcriptionally silent histone H3 tri-methyl K9 epigenetic mark at subcytotoxic concentrations. Taken together, these efforts identify and validate a hydroxyquinoline scaffold and a novel benzimidazole pyrazolone scaffold as tractable for entry into hit-to-lead chemical optimization campaigns.

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma
Du(*), J., Neuenschwander, M., Yu(*), Y., Dabritz(*), J. H., Neuendorff(*), N. R., Schleich(*), K., Bittner(*), A., Milanovic(*), M., Beuster(*), G., Radetzki, S., Specker, E., Reimann(*), M., Rosenbauer(*), F., Mathas(*), S., Lohneis(*), P., Hummel(*), M., Dörken(*), B., von Kries, J. P., Lee(*), S.; Schmitt(*), C. A.
Blood, 129:71-81

Tags: Screening Unit (von Kries)

Abstract: Classical Hodgkin lymphoma (cHL), although originating from B cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but it may also render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted a high-throughput pharmacological screening based on >28 000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote reexpression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of 2 of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the antileukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked reexpression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell non-Hodgkin lymphoma-tailored small-compound inhibitors ibrutinib and idelalisib. In essence, we report here a conceptually novel, redifferentiation-based treatment strategy for cHL.

A Chemical Disruptor of the ClpX Chaperone Complex Attenuates Multiresistant Staphylococcus aureus Virulence
Fetzer(*), C., Korotkov(*), V. S., Thanert(*), R., Lee(*), K. M., Neuenschwander, M., von Kries, J. P., Medina(*), E.; Sieber(*), S. A.
Angew Chem Int Ed Engl,

Tags: Screening Unit (von Kries)

Abstract: The Staphylococcus aureus ClpXP protease is an important regulator of cell homeostasis and virulence. Here we utilize a high-throughput screen against the ClpXP complex and identify a specific inhibitor of the ClpX chaperone that disrupts its oligomeric state. Synthesis of 34 derivatives revealed that the molecular scaffold is restrictive for diversification with only minor changes tolerated. Subsequent analysis of the most active compound revealed strong attenuation of S. aureus toxin production which was quantified via a customized MS-based assay platform. Transcriptome and whole proteome studies further confirmed the global reduction of virulence and unraveled characteristic signatures of protein expression in compound treated cells. Although these partially matched the pattern of ClpX knockout cells, further depletion of toxins was observed leading to the intriguing perspective that additional virulence pathways may be directly or indirectly addressed by the small molecule.

Small Molecules Targeting Human N-Acetylmannosamine Kinase
Hinderlich(*), S., Neuenschwander, M., Wratil(*), P. R., Oder, A., Lisurek, M., Nguyen(*), L. D., von Kries, J. P.; Hackenberger, C. P. R.

Tags: Chemical Biology II (Hackenberger), Screening Unit ( von Kries)

Abstract: N-Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. In search of effective inhibitors of MNK we applied high-throughput screening of drug-like small molecules. By applying different orthogonal assays for their validation we identified four potential MNK-specific inhibitors with IC50 values in the low-micromolar range. Molecular modelling of the inhibitors into the active site of MNK supports their binding to the sugar or the ATP-binding pocket of the enzyme or both. These compounds are promising for downregulation of the sialic acid content of glycoconjugates and for studying the functional contribution of sialic acids to disease development.

Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1
Juneja(*), M., Kobelt(*), D., Walther(*), W., Voss(*), C., Smith(*), J., Specker, E., Neuenschwander, M., Gohlke(*), B. O., Dahlmann(*), M., Radetzki, S., Preissner(*), R., von Kries, J. P., Schlag(*), P. M.; Stein(*), U.
PLoS biology, 15:e2000784

Tags: Screening Unit (von Kries)

Abstract: MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.

Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity
Wetzel(*), C., Pifferi(*), S., Picci(*), C., Gök(*), C., Hoffmann(*), D., Bali(*), K. K., Lampe, A., Lapatsina(*), L., Fleischer(*), R., Smith(*), E. S., Begay(*), V., Moroni(*), M., Estebanez(*), L., Kühnemund(*), J., Walcher(*), J., Specker, E., Neuenschwander, M., von Kries, J. P., Haucke, V., Kuner(*), R., Poulet(*), J. F., Schmoranzer(*), J., Poole(*), K.; Lewin(*), G. R.
Nat Neurosci, 20:209-218

Tags: Molecular Pharmacology and Cell Biology (Haucke), Screening Unit (von Kries)

Abstract: The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer-scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin-like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors in vivo. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy.

Loss of Ptpn11 (Shp2) drives satellite cells into quiescence
Griger(*), J., Schneider(*), R., Lahmann(*), I., Schöwel(*9, V., Keller(*), C., Spuler(*), S., Nazare, M.; Birchmeier(*), C.
Elife, 6

Tags: Medicinal Chemistry (Nazare)

Abstract: The equilibrium between proliferation and quiescence of myogenic progenitor and stem cells is tightly regulated to ensure appropriate skeletal muscle growth and repair. The non-receptor tyrosine phosphatase Ptpn11 (Shp2) is an important transducer of growth factor and cytokine signals. Here we combined complex genetic analyses, biochemical studies and pharmacological interference to demonstrate a central role of Ptpn11 in postnatal myogenesis of mice. Loss of Ptpn11 drove muscle stem cells out of the proliferative and into a resting state during muscle growth. This Ptpn11 function was observed in postnatal but not fetal myogenic stem cells. Furthermore, muscle repair was severely perturbed when Ptpn11 was ablated in stem cells due to a deficit in stem cell proliferation and survival. Our data demonstrate a molecular difference in the control of cell cycle withdrawal in fetal and postnatal myogenic stem cells, and assign to Ptpn11 signaling a key function in satellite cell activity.

A straightforward approach to N-substituted-2H-indazol-2-amines through reductive cyclization
Schöne, J., Abed, H. B., Christmann(*), M.; Nazare, M.
Tetrahedron Lett, 58:1633-1635

Tags: Medicinal Chemistry (Nazare)

Abstract: A versatile two-step, one-pot reaction to access N-substituted-2H-indazol-2-amine derivatives has been elaborated. A diverse set of analogues was obtained by a sequential hydrazone formation and reductive cyclization in moderate to good yields from readily available starting materials. The strategy tolerates a broad range of substitutions pattern and functional groups allowing further derivatizations. (C) 2017 Elsevier Ltd. All rights reserved.

Direct Experimental Evidence for Halogen-Aryl pi Interactions in Solution from Molecular Torsion Balances
Sun, H., Horatscheck, A., Martos, V., Bartetzko, M., Uhrig, U., Lentz, D., Schmieder, P.; Nazare, M.
Angew Chem Int Ed Engl, 56:6454-6458

Tags: Medicinal Chemistry (Nazare), Solution NMR (Schmieder), Computational Chemistry/ Drug Design (Kühne)

Abstract: We dissected halogen-aryl pi interactions experimentally using a bicyclic N-arylimide based molecular torsion balances system, which is based on the influence of the non-bonded interaction on the equilibria between folded and unfolded states. Through comparison of balances modulated by higher halogens with fluorine balances, we determined the magnitude of the halogen-aryl pi interactions in our unimolecular systems to be larger than -5.0 kJ mol-1 , which is comparable with the magnitude estimated in the biomolecular systems. Our study provides direct experimental evidence of halogen-aryl pi interactions in solution, which until now have only been revealed in the solid state and evaluated theoretically by quantum-mechanical calculations.

Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery
Dithmer, S., Staat, C., Müller, C., Ku(*), M. C., Pohlmann(*), A., Niendorf(*), T., Gehne, N., Fallier-Becker(*), P., Kittel(*), A., Walter(*), F. R., Veszelka(*), S., Deli(*), M. A., Blasig, R., Haseloff, R. F., Blasig, I. E.; Winkler, L.
Annals of the New York Academy of Sciences, 1397:169-184

Tags: Molecular Cell Physiology (Blasig, I.E.)

Abstract: The blood-brain barrier (BBB) formed by the microvascular endothelium limits cerebral drug delivery. The paraendothelial cleft is sealed by tight junctions (TJs) with a major contribution from claudin-5, which we selected as a target to modulate BBB permeability. For this purpose, drug-enhancer peptides were designed based on the first extracellular loop (ECL) of claudin-5 to allow transient BBB permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity to claudin-5) size-selectively (</=40 kDa) and reversibly (12-48 h) increased the permeability of brain endothelial and claudin-5-transfected epithelial cell monolayers. Upon peptide uptake, the number of TJ strand particles diminished, claudin-5 was downregulated and redistributed from cell-cell contacts to the cytosol, and the cell shape was altered. Cellular permeability of doxorubicin (cytostatic drug, 580 Da) was enhanced after peptide administration. Mouse studies (3.5 mumol/kg i.v.) confirmed that, for both C5C2 and a d-amino acid derivative, brain uptake of Gd-diethylene-triamine penta-acetic acid (547 Da) was enhanced within 4 h of treatment. On the basis of our functional data, circular dichroism measurements, molecular modeling, and docking experiments, we suggest an association model between beta-sheets flanked by alpha-helices, formed by claudin-5 ECLs, and the peptides. In conclusion, we identified claudin-5 peptidomimetics that improve drug delivery through endothelial and epithelial barriers expressing claudin-5.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)

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