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Ernst  Schonbrunn

Ernst Schonbrunn, PhD

Program: Drug Discovery

Research Program: Molecular Medicine Program

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  • Overview


    • Drug Discovery
    • Malignant Hematology
    • Molecular Medicine Program
    • Molecular Oncology & Drug Discovery Program

    Education & Training


    • Max-Planck Research Unit for Structural Molecular Biology, PhD - Biology/Crystallography


    • Max-Planck Research Unit for Structural Molecular Biology - Structural Molecular Biology
  • Research Interest

    Research from the Schönbrunn laboratory focuses on the elucidation of the structure-activity relationship of medicinally important proteins. We use protein crystallography combined with methods in biochemistry, molecular biology and medicinal chemistry to explore proteins at the atomic level. Our aim is to identify "weak sites" in those proteins that can be targeted by new inhibitors with potential as future drugs. The spectrum of prospective drug targets under investigation in our laboratory is diverse and growing continuously: Antibiotic targets such as MurA and EPSP synthase. Anti-cancer targets such as CDK2/cyclin A and glucometabolic enzymes. Neurodegenerative disease targets such as calpain. Male-contraceptive targets such as soluble adenylate cyclase. We generally follow two routes towards the discovery of novel inhibitors; both these approaches become interconnected if the target protein can be crystallized. The empirical approach involves the development of an assay suitable for high-throughput screening (HTS) of hundreds of thousands of small organic compounds for inhibitory activity. Thus discovered inhibitors (hits) will be scrutinized by structure-activity relationship (SAR) and kinetic studies until the most potent inhibitors with drug-like properties (leads) have been identified. The second route is the rational design of inhibitors based on the 3D atomic structure of the target protein. First, crystallization conditions suitable for reproducible growth of X-ray quality crystals need to be established. Then, the atomic structure of the target protein will be solved by crystallographic methods, bound with ligands such as substrates, known inhibitors or newly discovered HTS hits and leads. With this information in hand, we perform several computational studies (in silico design), such as molecular docking, to identify chemical scaffolds that satisfy the criteria for high inhibitory potential. During the entire inhibitor discovery process we closely collaborate with researchers of various disciplines, from synthetic organic chemistry to cell biology, to devise strategies for the optimization of the best inhibitors with respect to drug-like properties. Our expertise enables us to not only thoroughly characterize the molecular mode of action of inhibitors on proteins; we also perform mechanistic studies, for example to trap reaction intermediate states of enzyme-catalyzed reactions. Furthermore, we investigate the resistance of target proteins to known inhibitors. These studies complement the rational design approach, at the same time providing valuable information about the relationship of the protein's structure and function.

  • Publications

    • Morozova A, Chan SC, Bayle S, Sun L, Grassie D, Iermolaieva A, Kalaga MN, Frydman S, Sansil S, Schönbrunn E, Duckett D, Monastyrskyi A. Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties. Eur J Med Chem. 2024 Feb.266:116101. Pubmedid: 38232465.
    • Faber EB, Sun L, Tang J, Roberts E, Ganeshkumar S, Wang N, Rasmussen D, Majumdar A, Hirsch LE, John K, Yang A, Khalid H, Hawkinson JE, Levinson NM, Chennathukuzhi V, Harki DA, Schönbrunn E, Georg GI. Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding. Nat Commun. 2023 Jun.14(1):3213. Pubmedid: 37270540. Pmcid: PMC10239507.
    • Faber EB, Wang N, John K, Sun L, Wong HL, Burban D, Francis R, Tian D, Hong KH, Yang A, Wang L, Elsaid M, Khalid H, Levinson NM, Schönbrunn E, Hawkinson JE, Georg GI. Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice. J Med Chem. 2023 Feb.66(3):1928-1940. Pubmedid: 36701569.
    • Liao Y, Chin Chan S, Welsh EA, Fang B, Sun L, Schönbrunn E, Koomen JM, Duckett DR, Haura EB, Monastyrskyi A, Rix U. Chemical Proteomics with Novel Fully Functionalized Fragments and Stringent Target Prioritization Identifies the Glutathione-Dependent Isomerase GSTZ1 as a Lung Cancer Target. Acs Chem Biol. 2023 Feb.18(2):251-264. Pubmedid: 36630201.
    • Al Noman MA, Cuellar RAD, Kyzer JL, Chung SSW, Cheryala N, Holth TAD, Maitra S, Naqvi T, Wong HL, Schönbrunn E, Hawkinson JE, Wolgemuth DJ, Georg GI. Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception. Eur J Med Chem. 2023 Dec.261:115821. Pubmedid: 37776573.
    • Jiang J, Zhao PL, Sigua LH, Chan A, Schönbrunn E, Qi J, Georg GI. 1,4-Dihydropyridinebutyrolactone-derived ring-opened ester and amide analogs targeting BET bromodomains. Arch Pharm (Weinheim). 2022 Nov.355(11):e2200288. Pubmedid: 35941525. Pmcid: PMC9633406.
    • Giuliano AR, Pilon-Thomas S, Schell MJ, Abrahamsen M, Islam JY, Isaacs-Soriano K, Kennedy K, Dukes CW, Whiting J, Rathwell J, Hensel JA, Mangual LN, Schonbrunn E, Bikowitz M, Grassie D, Yang Y. SARS-CoV-2 Period Seroprevalence and Related Factors, Hillsborough County, Florida, USA, October 2020-March 2021. Emerg Infect Dis. 2022 Mar.28(3):556-563. Pubmedid: 35081021. Pmcid: PMC8888241.
    • Karim RM, Yang L, Chen L, Bikowitz MJ, Lu J, Grassie D, Shultz ZP, Lopchuk JM, Chen J, Schönbrunn E. Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain. J Med Chem. 2022 Mar.65(5):4182-4200. Pubmedid: 35191694.
    • Durbin AD, Wang T, Wimalasena VK, Zimmerman MW, Li D, Dharia NV, Mariani L, Shendy NAM, Nance S, Patel AG, Shao Y, Mundada M, Maxham L, Park PMC, Sigua LH, Morita K, Saur Conway A, Robichaud AL, Perez-Atayde AR, Bikowitz MJ, Quinn TR, Wiest OG, Easton J, Schonbrunn E, Bulyk ML, Abraham BJ, Stegmaier K, Look AT, Qi J. EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma. Cancer Discov. 2022 Mar.12(3):730-751. Pubmedid: 34772733. Pmcid: PMC8904277.
    • Jiang J, Sigua LH, Chan A, Kalra P, Pomerantz WCK, Schönbrunn E, Qi J, Georg GI. Dihydropyridine Lactam Analogs Targeting BET Bromodomains. Chemmedchem. 2022 Jan.17(1):e202100407. Pubmedid: 34932262. Pmcid: PMC8762755.
    • Guan X, Cheryala N, Karim RM, Chan A, Berndt N, Qi J, Georg GI, Schönbrunn E. Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity. J Med Chem. 2022 Aug.65(15):10441-10458. Pubmedid: 35867655.
    • Zahid H, Buchholz CR, Singh M, Ciccone MF, Chan A, Nithianantham S, Shi K, Aihara H, Fischer M, Schönbrunn E, Dos Santos CO, Landry JW, Pomerantz WCK. New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition. J Med Chem. 2021 Sep.64(18):13902-13917. Pubmedid: 34515477. Pmcid: PMC9012132.
    • Xiao T, Sun L, Zhang M, Li Z, Haura EB, Schonbrunn E, Ji H. Synthesis and structural characterization of a monocarboxylic inhibitor for GRB2 SH2 domain. Bioorg Med Chem Lett. 2021 Nov.51:128354. Pubmedid: 34506932. Pmcid: PMC8526398.
    • Muthengi A, Wimalasena VK, Yosief HO, Bikowitz MJ, Sigua LH, Wang T, Li D, Gaieb Z, Dhawan G, Liu S, Erickson J, Amaro RE, Schönbrunn E, Qi J, Zhang W. Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors. J Med Chem. 2021 May.64(9):5787-5801. Pubmedid: 33872011. Pmcid: PMC8856734.
    • Lee JC, Hong KH, Becker A, Tash JS, Schönbrunn E, Georg GI. Tetrahydroindazole inhibitors of CDK2/cyclin complexes. Eur J Med Chem. 2021 Mar.214:113232. Pubmedid: 33550184. Pmcid: PMC7954990.
    • Davis RR, Li B, Yun SY, Chan A, Nareddy P, Gunawan S, Ayaz M, Lawrence HR, Reuther GW, Lawrence NJ, Schönbrunn E. Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof. J Med Chem. 2021 Feb.64(4):2228-2241. Pubmedid: 33570945. Pmcid: PMC8327781.
    • Olson NM, Kroc S, Johnson JA, Zahid H, Ycas PD, Chan A, Kimbrough JR, Kalra P, Schönbrunn E, Pomerantz WCK. NMR Analyses of Acetylated H2A.Z Isoforms Identify Differential Binding Interactions with the Bromodomain of the NURF Nucleosome Remodeling Complex. Biochemistry-Us. 2020 May.59(20):1871-1880. Pubmedid: 32356653. Pmcid: PMC7771244.
    • Karim RM, Chan A, Zhu JY, Schönbrunn E. Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains. J Med Chem. 2020 Mar.63(6):3227-3237. Pubmedid: 32091206. Pmcid: PMC7771325.
    • Huang Q, Chen L, Schonbrunn E, Chen J. MDMX inhibits casein kinase 1α activity and stimulates Wnt signaling. Embo J. 2020 Jul.39(14):e104410. Pubmedid: 32511789. Pmcid: PMC7361285.
    • Li Q, Karim RM, Cheng M, Das M, Chen L, Zhang C, Lawrence HR, Daughdrill GW, Schonbrunn E, Ji H, Chen J. Inhibition of p53 DNA binding by a small molecule protects mice from radiation toxicity. Oncogene. 2020 Jul.39(29):5187-5200. Pubmedid: 32555331. Pmcid: PMC7398576.
    • Ycas PD, Zahid H, Chan A, Olson NM, Johnson JA, Talluri SK, Schonbrunn E, Pomerantz WCK. New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development. Org Biomol Chem. 2020 Jul.18(27):5174-5182. Pubmedid: 32588860. Pmcid: PMC7393680.
    • Liu X, Huang Q, Chen L, Zhang H, Schonbrunn E, Chen J. Tumor-derived CK1α mutations enhance MDMX inhibition of p53. Oncogene. 2020 Jan.39(1):176-186. Pubmedid: 31462704. Pmcid: PMC7739390.
    • Hanna CB, Mudaliar D, John K, Allen CL, Sun L, Hawkinson JE, Schönbrunn E, Georg GI, Jensen JT. Development of WEE2 kinase inhibitors as novel non-hormonal female contraceptives that target meiosis†. Biol Reprod. 2020 Aug.103(2):368-377. Pubmedid: 32667031. Pmcid: PMC7401407.
    • Hanna CB, Yao S, Martin M, Schönbrunn E, Georg GI, Jensen JT, Cuellar RAD. Identification and Screening of Selective WEE2 Inhibitors to Develop Non-Hormonal Contraceptives that Specifically Target Meiosis. ChemistrySelect. 2019 Dec.4(45):13363-13369. Pubmedid: 32190728. Pmcid: PMC7079731.
    • Divakaran A, Talluri SK, Ayoub AM, Mishra N, Cui H, Widen JC, Berndt N, Zhu JY, Carlson AS, Topczewski JJ, Schönbrunn E, Harki DA, Pomerantz WCK. Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. J Med Chem. 2018 Oct.61(20):9316-9334. Pubmedid: 30253095. Pmcid: PMC6245549.
    • Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK, Schönbrunn E. Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. Acs Chem Biol. 2018 Mar.13(3):582-590. Pubmedid: 29240402. Pmcid: PMC6089219.
    • Nerlakanti N, Yao J, Nguyen DT, Patel AK, Eroshkin AM, Lawrence HR, Ayaz M, Kuenzi BM, Agarwal N, Chen Y, Gunawan S, Karim RM, Berndt N, Puskas J, Magliocco AM, Coppola D, Dhillon J, Zhang J, Shymalagovindarajan S, Rix U, Kim Y, Perera R, Lawrence NJ, Schonbrunn E, Mahajan K. Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer. Mol Cancer Ther. 2018 Dec.17(12):2796-2810. Pubmedid: 30242092. Pmcid: PMC6528782.
    • Paulson CN, Guan X, Ayoub AM, Chan A, Karim RM, Pomerantz WCK, Schönbrunn E, Georg GI, Hawkinson JE. Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe. ACS Med Chem Lett. 2018 Dec.9(12):1223-1229. Pubmedid: 30613330. Pmcid: PMC6295860.
    • Akuffo AA, Alontaga AY, Metcalf R, Beatty MS, Becker A, McDaniel JM, Hesterberg RS, Goodheart WE, Gunawan S, Ayaz M, Yang Y, Karim MR, Orobello ME, Daniel K, Guida W, Yoder JA, Rajadhyaksha AM, Schonbrunn E, Lawrence HR, Lawrence NJ, Epling-Burnette PK. Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon. J Biol Chem. 2018 Apr.293(16):6187-6200. Pubmedid: 29449372. Pmcid: PMC5912449.
    • Zhu JY, Cuellar RAD, Berndt N, Lee HE, Olesen SH, Martin MP, Jensen JT, Georg GI, Schönbrunn E. Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. J Med Chem. 2017 Sep.60(18):7863-7875. Pubmedid: 28792760. Pmcid: PMC6200136.
    • Xu Y, Greenberg RA, Schonbrunn E, Wang PJ. Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the single-stranded DNA-binding replication protein A complex and DNA double-strand breaks. Biol Reprod. 2017 May.96(5):1096-1104. Pubmedid: 28453612. Pmcid: PMC6355104.
    • Ember SW, Lambert QT, Berndt N, Gunawan S, Ayaz M, Tauro M, Zhu JY, Cranfill PJ, Greninger P, Lynch CC, Benes CH, Lawrence HR, Reuther GW, Lawrence NJ, Schonbrunn E. Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics. Mol Cancer Ther. 2017 Jun.16(6):1054-1067. Pubmedid: 28336808. Pmcid: PMC5457702.
    • Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewski AJ, Gee CT, Zhao P, Zhu JY, Berndt N, Offei-Addo NK, Scott TG, Qi J, Bradner JE, Ward TR, Schönbrunn E, Georg GI, Pomerantz WCK. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen. J Med Chem. 2017 Jun.60(12):4805-4817. Pubmedid: 28535045. Pmcid: PMC5558211.
    • Wright G, Golubeva V, Remsing Rix LL, Berndt N, Luo Y, Ward GA, Gray JE, Schönbrunn E, Lawrence HR, Monteiro ANA, Rix U. Dual Targeting of WEE1 and PLK1 by AZD1775 Elicits Single Agent Cellular Anticancer Activity. Acs Chem Biol. 2017 Jul.12(7):1883-1892. Pubmedid: 28557434. Pmcid: PMC5551971.
    • Georg GI, Gu X, Gupta V, Yang Y, Zhu J, Carlson E, Kingsley C, Tash J, Schonbrunn E, Hawkinson J. Structure-Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2. Chemmedchem. 2017 Dec.12(23):1977-1984. Pubmedid: 28975712. Pmcid: PMC5725710.
    • Berndt N, Karim RM, Schönbrunn E. Advances of small molecule targeting of kinases. Curr Opin Chem Biol. 2017 Aug.39:126-132. Pubmedid: 28732278. Pmcid: PMC5728163.
    • Allen BK, Mehta S, Ember SWJ, Zhu JY, Schönbrunn E, Ayad NG, Schürer SC. Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations. ACS Omega. 2017 Aug.2(8):4760-4771. Pubmedid: 28884163. Pmcid: PMC5579542.
    • Karim RM, Schönbrunn E. An Advanced Tool To Interrogate BRD9. J Med Chem. 2016 May.59(10):4459-4461. Pubmedid: 27120693.
    • Olesen SH, Zhu JY, Martin MP, Schönbrunn E. Discovery of Diverse Small-Molecule Inhibitors of Mammalian Sterile20-like Kinase 3 (MST3). Chemmedchem. 2016 Jun.11(11):1137-1144. Pubmedid: 27135311. Pmcid: PMC7771544.
    • Koblan LW, Buckley DL, Ott CJ, Fitzgerald ME, Ember SW, Zhu JY, Liu S, Roberts JM, Remillard D, Vittori S, Zhang W, Schonbrunn E, Bradner JE. Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET. Chemmedchem. 2016 Dec.11(23):2575-2581. Pubmedid: 27862999.
    • Mishra NK, Urick AK, Ember SW, Schönbrunn E, Pomerantz WC. Correction to Letter: Fluorinated Aromatic Amino Acids Are Sensitive (19)F NMR Probes for Bromodomain-Ligand Interactions. Acs Chem Biol. 2016 Apr.11(4):1149. Pubmedid: 26836633. Pmcid: PMC4835746.
    • Allen BK, Mehta S, Ember SW, Schonbrunn E, Ayad N, Schürer SC. Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4. Sci Rep. 2015 Nov.5:16924. Pubmedid: 26596901. Pmcid: PMC4657038.
    • Olesen SH, Ingles DJ, Zhu JY, Martin MP, Betzi S, Georg GI, Tash JS, Schönbrunn E. Stability of the human Hsp90-p50Cdc37 chaperone complex against nucleotides and Hsp90 inhibitors, and the influence of phosphorylation by casein kinase 2. Molecules. 2015 Jan.20(1):1643-1660. Pubmedid: 25608045. Pmcid: PMC4601640.
    • Chen L, Borcherds W, Wu S, Becker A, Schonbrunn E, Daughdrill GW, Chen J. Autoinhibition of MDMX by intramolecular p53 mimicry. Proc Natl Acad Sci U S A. 2015 Apr.112(15):4624-4629. Pubmedid: 25825738. Pmcid: PMC4403185.
    • Yang H, Lawrence HR, Kazi A, Gevariya H, Patel R, Luo Y, Rix U, Schonbrunn E, Lawrence NJ, Sebti SM. Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation. Oncotarget. 2014 May.5(10):2947-2961. Pubmedid: 24930769. Pmcid: PMC4102782.
    • Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E. Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. Acs Chem Biol. 2014 May.9(5):1160-1171. Pubmedid: 24568369. Pmcid: PMC4032195.
    • Mishra NK, Urick AK, Ember S, Schonbrunn E, Pomerantz WC. Fluorinated aromatic amino acids are sensitive 19F NMR probes for bromodomain-ligand interactions. Acs Chem Biol. 2014 Dec.9(12):2755-2760. Pubmedid: 25290579. Pmcid: PMC4273984.
    • Olesen SH, Ingles DJ, Yang Y, Schönbrunn E. Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin. J Basic Microbiol. 2014 Apr.54(4):322-326. Pubmedid: 23686727. Pmcid: PMC4610358.
    • Martin MP, Olesen SH, Georg GI, Schonbrunn E. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. Acs Chem Biol. 2013 Nov.8(11):2360-2365. Pubmedid: 24007471. Pmcid: PMC3846258.
    • Schonbrunn E, Betzi S, Alam R, Martin MP, Becker A, Han H, Francis R, Chakrasali R, Jakkaraj S, Kazi A, Sebti SM, Cubitt CL, Gebhard AW, Hazlehurst LA, Tash JS, Georg GI. Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. J Med Chem. 2013 May.56(10):3768-3782. Pubmedid: 23600925. Pmcid: PMC3714109.
    • Lawrence HR, Martin MP, Luo Y, Pireddu R, Yang H, Gevariya H, Ozcan S, Zhu JY, Kendig R, Rodriguez M, Elias R, Cheng JQ, Sebti SM, Schonbrunn E, Lawrence NJ. Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors. J Med Chem. 2012 Sep.55(17):7392-7416. Pubmedid: 22803810. Pmcid: PMC4429609.
    • Martin MP, Alam R, Betzi S, Ingles DJ, Zhu JY, Schönbrunn E. A novel approach to the discovery of small-molecule ligands of CDK2. Chembiochem. 2012 Sep.13(14):2128-2136. Pubmedid: 22893598. Pmcid: PMC3483082.
    • Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, Schönbrunn E, Lawrence NJ, Sebti SM. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res. 2012 Oct.72(19):5025-5034. Pubmedid: 22846914. Pmcid: PMC3463757.
    • Doi K, Li R, Sung SS, Wu H, Liu Y, Manieri W, Krishnegowda G, Awwad A, Dewey A, Liu X, Amin S, Cheng C, Qin Y, Schonbrunn E, Daughdrill G, Loughran TP, Sebti S, Wang HG. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem. 2012 Mar.287(13):10224-10235. Pubmedid: 22311987. Pmcid: PMC3323047.
    • Li R, Martin MP, Liu Y, Wang B, Patel RA, Zhu JY, Sun N, Pireddu R, Lawrence NJ, Li J, Haura EB, Sung SS, Guida WC, Schonbrunn E, Sebti SM. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J Med Chem. 2012 Mar.55(5):2474-2478. Pubmedid: 22272748. Pmcid: PMC4516226.
    • Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM, Lawrence NJ. Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun.3(6):699-709. Pubmedid: 23275831. Pmcid: PMC3531244.
    • Wu S, Chen L, Becker A, Schonbrunn E, Chen J. Casein kinase 1α regulates an MDMX intramolecular interaction to stimulate p53 binding. Mol Cell Biol. 2012 Dec.32(23):4821-4832. Pubmedid: 23028042. Pmcid: PMC3497597.
    • Martin MP, Zhu JY, Lawrence HR, Pireddu R, Luo Y, Alam R, Ozcan S, Sebti SM, Lawrence NJ, Schönbrunn E. A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. Acs Chem Biol. 2012 Apr.7(4):698-706. Pubmedid: 22248356. Pmcid: PMC4429595.
    • Lee JC, Francis S, Dutta D, Gupta V, Yang Y, Zhu JY, Tash JS, Schönbrunn E, Georg GI. Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases. J Org Chem. 2012 Apr.77(7):3082-3098. Pubmedid: 22432895. Pmcid: PMC3431965.
    • Zhu JY, Yang Y, Han H, Betzi S, Olesen SH, Marsilio F, Schönbrunn E. Functional consequence of covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA). J Biol Chem. 2012 Apr.287(16):12657-12667. Pubmedid: 22378791. Pmcid: PMC3339971.
    • Betzi S, Alam R, Martin M, Lubbers DJ, Han H, Jakkaraj SR, Georg GI, Schönbrunn E. Discovery of a potential allosteric ligand binding site in CDK2. Acs Chem Biol. 2011 May.6(5):492-501. Pubmedid: 21291269. Pmcid: PMC3098941.
    • Pollegioni L, Schonbrunn E, Siehl D. Molecular basis of glyphosate resistance-different approaches through protein engineering. FEBS J. 2011 Aug.278(16):2753-2766. Pubmedid: 21668647. Pmcid: PMC3145815.
    • Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ, Sebti SM. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 2010 Nov.17(11):1795-1804. Pubmedid: 20489726. Pmcid: PMC2952662.
    • Han H, Yang Y, Olesen SH, Becker A, Betzi S, Schönbrunn E. The fungal product terreic acid is a covalent inhibitor of the bacterial cell wall biosynthetic enzyme UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) . Biochemistry-Us. 2010 May.49(19):4276-4282. Pubmedid: 20392080. Pmcid: PMC2884014.
    • Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar.5(3):e9646. Pubmedid: 20333297. Pmcid: PMC2841635.
    • Phan J, Li Z, Kasprzak A, Li B, Sebti S, Guida W, Schönbrunn E, Chen J. Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J Biol Chem. 2010 Jan.285(3):2174-2183. Pubmedid: 19910468. Pmcid: PMC2804373.
    • Alontaga AY, Rodriguez JC, Schönbrunn E, Becker A, Funke T, Yukl ET, Hayashi T, Stobaugh J, Moënne-Loccoz P, Rivera M. Structural characterization of the hemophore HasAp from Pseudomonas aeruginosa: NMR spectroscopy reveals protein-protein interactions between Holo-HasAp and hemoglobin. Biochemistry-Us. 2009 Jan.48(1):96-109. Pubmedid: 19072037. Pmcid: PMC2666852.
    • Funke T, Yang Y, Han H, Healy-Fried M, Olesen S, Becker A, Schonbrunn E. Structural basis of glyphosate resistance resulting from the double mutation Thr97 -> Ile and Pro101 -> Ser in 5-enolpyruvylshikimate-3-phosphate synthase from Escherichia coli. J Biol Chem. 2009 Apr.284(15):9854-9860. Pubmedid: 19211556. Pmcid: PMC2665107.
    • Wang A, Rodríguez JC, Han H, Schönbrunn E, Rivera M. X-ray crystallographic and solution state nuclear magnetic resonance spectroscopic investigations of NADP+ binding to ferredoxin NADP reductase from Pseudomonas aeruginosa. Biochemistry-Us. 2008 Aug.47(31):8080-8093. Pubmedid: 18605699. Pmcid: PMC2792877.
    • Wang A, Zeng Y, Han H, Weeratunga S, Morgan B, Moenne-Loccoz P, Schonbrunn E, Rivera M. Biochemical and structural characterization of Pseudomonas aeruginosa Bfd and FPR: ferredoxin NADP+ reductase and not ferredoxin is the redox partner of heme oxygenase under iron-starvation conditions. Biochemistry-Us. 2007 Oct.46(43):12198-12211. Pubmedid: 17915950.
    • Healy-Fried M, Funke T, Priestman M, Han H, Schonbrunn E. Structural basis of glyphosate tolerance resulting from mutations of Pro101 in Escherichia coli 5-enolpyruvylshikimate-3-phosphate synthase. J Biol Chem. 2007 Nov.282(45):32949-32955. Pubmedid: 17855366.
    • Funke T, Healy-Fried M, Han H, Alberg D, Bartlett P, Schonbrunn E. Differential inhibition of class I and class II 5-enolpyruvylshikimate-3-phosphate synthases by tetrahedral reaction intermediate analogues. Biochemistry-Us. 2007 Nov.46(46):13344-13351. Pubmedid: 17958399.
    • Li Q, Hanzlik R, Weaver R, Schonbrunn E. Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core. Biochemistry. 2006 Jan.45(3):701-708. Pubmedid: 16411745.
    • Funke T, Han H, Healy-Fried ML, Fischer M, Schonbrunn E. Molecular basis for the herbicide resistance of Roundup Ready crops. Proc Natl Acad Sci U S A. 2006 Aug.103(35):13010-13015. Pubmedid: 16916934. Pmcid: PMC1559744.
    • Priestman M, Healy M, Funke T, Becker A, Schonbrunn E. Molecular basis for the glyphosate-insensitivity of the reaction of 5-enolpyruvylshikimate 3-phosphate synthase with shikimate. FEBS Lett. 2005 Oct.579(25):5773-5780. Pubmedid: 16225867.
    • Priestman MA, Healy ML, Becker A, Alberg DG, Bartlett PA, Lushington GH, Schönbrunn E. Interaction of phosphonate analogues of the tetrahedral reaction intermediate with 5-enolpyruvylshikimate-3-phosphate synthase in atomic detail. Biochemistry. 2005 Mar.44(9):3241-3248. Pubmedid: 15736934.
    • Priestman M, Funke T, Singh I, Crupper S, Schonbrunn E. 5-Enolpyruvylshikimate-3-phosphate synthase from Staphylococcus aureus is insensitive to glyphosate. FEBS Lett. 2005 Jan.579(3):728-732. Pubmedid: 15670836.
    • Eschenburg S, Priestman M, Schonbrunn E. Evidence that the fosfomycin target Cys115 in UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is essential for product release. J Biol Chem. 2005 Feb.280(5):3757-3763. Pubmedid: 15531591.
    • Eschenburg S, Priestman M, Abdul-Latif F, Delachaume C, Fassy F, Schonbrunn E. A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). J Biol Chem. 2005 Apr.280(14):14070-14075. Pubmedid: 15701635.
    • Eschenburg S, Kabsch W, Healy M, Schonbrunn E. A new view of the mechanisms of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) and 5-enolpyruvylshikimate-3-phosphate synthase (AroA) derived from X-ray structures of their tetrahedral reaction intermediate states. J Biol Chem. 2003 Dec.278(49):49215-49222. Pubmedid: 13129913.
    • Eschenburg S, Healy M, Priestman M, Lushington G, Schonbrunn E. How the mutation glycine96 to alanine confers glyphosate insensitivity to 5-enolpyruvyl shikimate-3-phosphate synthase from Escherichia coli. Planta. 2002 Nov.216(1):129-135. Pubmedid: 12430021.
    • Schonbrunn E, Eschenburg S, Shuttleworth W, Schloss J, Amrhein N, Evans J, Kabsch W. Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail. Proc Natl Acad Sci U S A. 2001 Feb.98(4):1376-1380. Pubmedid: 11171958.
    • Schonbrunn E, Eschenburg S, Krekel F, Luger K, Amrhein N. Role of the loop containing residue 115 in the induced-fit mechanism of the bacterial cell wall biosynthetic enzyme MurA. Biochemistry. 2000 Mar.39(9):2164-2173. Pubmedid: 10694381.
    • Schonbrunn E, Eschenburg S, Luger K, Kabsch W, Amrhein N. Structural basis for the interaction of the fluorescence probe 8-anilino-1-naphthalene sulfonate (ANS) with the antibiotic target MurA. Proc Natl Acad Sci U S A. 2000 Jun.97(12):6345-6349. Pubmedid: 10823915.
    • Eschenburg S, Schonbrunn E. Comparative X-ray analysis of the un-liganded fosfomycin-target murA. Proteins. 2000 Aug.40(2):290-298. Pubmedid: 10842342.
    • Schonbrunn E, Phlippen W, Trinczek B, Sack S, Eschenburg S, Mandelkow E, Mandelkow E. Crystallization of a macromolecular ring assembly of tubulin liganded with the anti-mitotic drug podophyllotoxin. J Struct Biol. 1999 Dec.128(2):211-215. Pubmedid: 10600574.
    • Macheroux P, Schonbrunn E, Svergun D, Volkov V, Koch M, Bornemann S, Thorneley R. Evidence for a major structural change in Escherichia coli chorismate synthase induced by flavin and substrate binding. Biochem J. 1998 Oct.335 ( Pt 2):319-327. Pubmedid: 9761730 .
    • Schonbrunn E, Svergun D, Amrhein N, Koch M. Studies on the conformational changes in the bacterial cell wall biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyltransferase (MurA). Eur J Biochem. 1998 Apr.253(2):406-412. Pubmedid: 9654090 .
    • Kozielski F, Schonbrunn E, Sack S, Muller J, Brady S, Mandelkow E. Crystallization and preliminary X-ray analysis of the single-headed and double-headed motor protein kinesin. J Struct Biol. 1997 Jun.119(1):28-34. Pubmedid: 9216086 .
    • Kozielski F, Sack S, Marx A, Thormahlen M, Schonbrunn E, Biou V, Thompson A, Mandelkow E, Mandelkow E. The crystal structure of dimeric kinesin and implications for microtubule-dependent motility. Cell. 1997 Dec.91(7):985-994. Pubmedid: 9428521 .
    • Schonbrunn E, Sack S, Eschenburg S, Perrakis A, Krekel F, Amrhein N, Mandelkow E. Crystal structure of UDP-N-acetylglucosamine enolpyruvyltransferase, the target of the antibiotic fosfomycin. Structure. 1996 Sep.4(9):1065-1075. Pubmedid: 8805592 .
    • Sack S, Dauter Z, Wanke C, Amrhein N, Mandelkow E, Schonbrunn E. Crystallization and preliminary X-ray diffraction analysis of UDP-N-acetylglucosamine enolpyruvyltransferase of Enterobacter cloacae. J Struct Biol. 1996 Jul.117(1):73-76. Pubmedid: 8776890 .
    • Schweers O, Schonbrunn-Hanebeck E, Marx A, Mandelkow E. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem. 1994 Sep.269(39):24290-24297. Pubmedid: 7929085 .
    • Schonbrunn-Hanebeck E, Laber B, Amrhein N. Slow-binding inhibition of the Escherichia coli pyruvate dehydrogenase multienzyme complex by acetylphosphinate. Biochemistry. 1990 May.29(20):4880-4885. Pubmedid: 2194562 .
  • Grants

    • Title: Selective Targeting of TAF1 Function in Acute Myeloid Leukemia
      Sponsor: Nat Institutes of Health
      PI (Contact): Schonbrunn, E., PI (MPI): Chen, J., PI (MPI): Lopchuk, J.

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