Publications | Structural Genomics Consortium

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.

Xiong Y, Li F, Babault N, Dong A, Zeng H, Wu H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b01645

Publication date: January 30, 2017

The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

He Y, Selvaraju S, Curtin ML, Jakob CG, Zhu H, Comess KM, Shaw B, The J, Lima-Fernandes E, Szewczyk MM, Cheng D, Klinge KL, Li HQ, Pliushchev M, Algire MA, Maag D, Guo J, Dietrich J, Panchal SC, Petros AM, Sweis RF, Torrent M, Bigelow LJ, Senisterra G, Li F, Kennedy S, Wu Q, Osterling DJ, Lindley DJ, Gao W, Galasinski S, Barsyte-Lovejoy D, Vedadi M, Buchanan FG, Arrowsmith CH, Chiang GG, Sun C, Pappano WN

Nat. Chem. Biol.. doi: 10.1038/nchembio.2306

Publication date: January 30, 2017

PMID: 28135237

Discovery and structure activity relationship of the first potent cryptosporidium FIKK kinase inhibitor.

Osman KT, Ye J, Shi Z, Toker C, Lovato D, Jumani RS, Zuercher W, Huston CD, Edwards AM, Lautens M, Santhakumar V, Hui R

Bioorg. Med. Chem.. doi: 10.1016/j.bmc.2017.01.036

Publication date: January 24, 2017

PMID: 28162900

The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.

Bromberg KD, Mitchell TR, Upadhyay AK, Jakob CG, Jhala MA, Comess KM, Lasko LM, Li C, Tuzon CT, Dai Y, Li F, Eram MS, Nuber A, Soni NB, Manaves V, Algire MA, Sweis RF, Torrent M, Schotta G, Sun C, Michaelides MR, Shoemaker AR, Arrowsmith CH, Brown PJ, Santhakumar V, Martin A, Rice JC, Chiang GG, Vedadi M, Barsyte-Lovejoy D, Pappano WN

Nat. Chem. Biol.. doi: 10.1038/nchembio.2282

Publication date: January 23, 2017

PMID: 28114273

Target engagement: Shining a light.

Huber KV

Nat. Chem. Biol.. 13(2):133-134. doi: 10.1038/nchembio.2295

Publication date: January 19, 2017

PMID: 28103226

Insights into the RecQ helicase mechanism revealed by the structure of the helicase domain of human RECQL5.

Newman JA, Aitkenhead H, Savitsky P, Gileadi O

Nucleic Acids Res.. doi: 10.1093/nar/gkw1362

Publication date: January 18, 2017

PMID: 28100692

Molecular insights into lipid-assisted Ca(2+) regulation of the TRP channel Polycystin-2.

Wilkes M, Madej MG, Kreuter L, Rhinow D, Heinz V, De Sanctis S, Ruppel S, Richter RM, Joos F, Grieben M, Pike AC, Huiskonen JT, Carpenter EP, Kühlbrandt W, Witzgall R, Ziegler C

Nat. Struct. Mol. Biol.. doi: 10.1038/nsmb.3357

Publication date: January 16, 2017

PMID: 28092368

Chemical Probes Targeting Epigenetic Proteins: Applications Beyond Oncology.

Ackloo S, Brown PJ, Müller S

Epigenetics. 0. doi: 10.1080/15592294.2017.1279371

Publication date: January 12, 2017

PMID: 28080202

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies.

Igoe N, Bayle ED, Fedorov O, Tallant C, Savitsky P, Rogers C, Owen DR, Deb G, Somervaille TC, Andrews DM, Jones N, Cheasty A, Ryder H, Brennan PE, Müller S, Knapp S, Fish PV

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b01583

Publication date: January 9, 2017

PMID: 28068087

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma.

Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, Hu Y, Ma A, Jin J, Mazur SJ, Lam N, Souza BK, Giannini G, Hager GL, Arrowsmith CH, Khan J, Appella E, Thiele CJ

Cancer Cell. 31(1):50-63. doi: 10.1016/j.ccell.2016.12.002

Publication date: January 9, 2017

PMID: 28073004

Functions of bromodomain-containing proteins and their roles in homeostasis and cancer.

Fujisawa T, Filippakopoulos P

Nat. Rev. Mol. Cell Biol.. doi: 10.1038/nrm.2016.143

Publication date: January 5, 2017

PMID: 28053347

Structure and inhibitor specificity of the PCTAIRE-family kinase CDK16.

Dixon-Clarke SE, Shehata SN, Krojer T, Sharpe TD, von Delft F, Sakamoto K, Bullock AN

Biochem. J.. doi: 10.1042/BCJ20160941

Publication date: January 5, 2017

PMID: 28057719

Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation.

Scheer S, Medina TS, Murison A, Taves MD, Antignano F, Chenery A, Soma KK, Perona-Wright G, Lupien M, Arrowsmith CH, De Carvalho DD, Zaph C

J. Leukoc. Biol.. doi: 10.1189/jlb.3MA0716-334RR

Publication date: December 29, 2016

PMID: 28034915

Predictions of ligand selectivity from absolute binding free energy calculations.

Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC

J. Am. Chem. Soc.. doi: 10.1021/jacs.6b11467

Publication date: December 23, 2016

PMID: 28009512

Identification of CLK1 Inhibitors by a Fragment-linking Based Virtual Screening.

Walter A, Chaikuad A, Loaëc N, Preu L, Knapp S, Meijer L, Kunick C, Koch O

Mol Inform. doi: 10.1002/minf.201600123

Publication date: December 21, 2016

PMID: 28000414

Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2).

Grieben M, Pike AC, Shintre CA, Venturi E, El-Ajouz S, Tessitore A, Shrestha L, Mukhopadhyay S, Mahajan P, Chalk R, Burgess-Brown NA, Sitsapesan R, Huiskonen JT, Carpenter EP

Nat. Struct. Mol. Biol.. doi: 10.1038/nsmb.3343

Publication date: December 19, 2016

PMID: 27991905

BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells.

Nagarajan S, Bedi U, Budida A, Hamdan FH, Mishra VK, Najafova Z, Xie W, Alawi M, Indenbirken D, Knapp S, Chiang CM, Grundhoff A, Kari V, Scheel CH, Wegwitz F, Johnsen SA

Nucleic Acids Res.. doi: 10.1093/nar/gkw1276

Publication date: December 15, 2016

PMID: 27980063

Discovery of a PCAF Bromodomain Chemical Probe.

Moustakim M, Clark PG, Trulli L, Fuentes de Arriba AL, Ehebauer MT, Chaikuad A, Murphy EJ, Mendez-Johnson J, Daniels D, Hou CD, Lin YH, Walker JR, Hui R, Yang H, Dorrell L, Rogers CM, Monteiro OP, Fedorov O, Huber KV, Knapp S, Heer J, Dixon DJ, Brennan PE

Angew. Chem. Int. Ed. Engl.. doi: 10.1002/anie.201610816

Publication date: December 14, 2016

PMID: 27966810

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Torchia J, Golbourn B, Feng S, Ho KC, Sin-Chan P, Vasiljevic A, Norman JD, Guilhamon P, Garzia L, Agamez NR, Lu M, Chan TS, Picard D, de Antonellis P, Khuong-Quang DA, Planello AC, Zeller C, Barsyte-Lovejoy D, Lafay-Cousin L, Letourneau L, Bourgey M, Yu M, Gendoo DM, Dzamba M, Barszczyk M, Medina T, Riemenschneider AN, Morrissy AS, Ra YS, Ramaswamy V, Remke M, Dunham CP, Yip S, Ng HK, Lu JQ, Mehta V, Albrecht S, Pimentel J, Chan JA, Somers GR, Faria CC, Roque L, Fouladi M, Hoffman LM, Moore AS, Wang Y, Choi SA, Hansford JR, Catchpoole D, Birks DK, Foreman NK, Strother D, Klekner A, Bognár L, Garami M, Hauser P, Hortobágyi T, Wilson B, Hukin J, Carret AS, Van Meter TE, Hwang EI, Gajjar A, Chiou SH, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheinemann K, Fleming AJ, Johnston DL, Michaud J, Zelcer S, Hammond R, Afzal S, Ramsay DA, Sirachainan N, Hongeng S, Larbcharoensub N, Grundy RG, Lulla RR, Fangusaro JR, Druker H, Bartels U, Grant R, Malkin D, McGlade CJ, Nicolaides T, Tihan T, Phillips J, Majewski J, Montpetit A, Bourque G, Bader GD, Reddy AT, Gillespie GY, Warmuth-Metz M, Rutkowski S, Tabori U, Lupien M, Brudno M, Schüller U, Pietsch T, Judkins AR, Hawkins CE, Bouffet E, Kim SK, Dirks PB, Taylor MD, Erdreich-Epstein A, Arrowsmith CH, De Carvalho DD, Rutka JT, Jabado N, Huang A

Cancer Cell. 30(6):891-908. doi: 10.1016/j.ccell.2016.11.003

Publication date: December 12, 2016

PMID: 27960086

CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation.

Olzscha H, Fedorov O, Kessler BM, Knapp S, La Thangue NB

Cell Chem Biol. doi: 10.1016/j.chembiol.2016.11.009

Publication date: December 10, 2016

PMID: 27989401

Functional and structural characterization of a novel putative cysteine protease cell wall-modifying multi-domain enzyme selected from a microbial metagenome.

Faheem M, Martins-de-Sa D, Vidal JF, Álvares AC, Brandão-Neto J, Bird LE, Tully MD, von Delft F, Souto BM, Quirino BF, Freitas SM, Barbosa JA

Sci Rep. 6:38031. doi: 10.1038/srep38031

Publication date: December 9, 2016

PMID: 27934875

Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.

Navratilova I, Aristotelous T, Picaud S, Chaikuad A, Knapp S, Filappakopoulos P, Hopkins AL

ACS Med Chem Lett. 7(12):1213-1218. doi: 10.1021/acsmedchemlett.6b00154

Publication date: December 8, 2016

PMID: 27994766

Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8.

Judge RA, Zhu H, Upadhyay AK, Bodelle PM, Hutchins CW, Torrent M, Marin VL, Yu W, Vedadi M, Li F, Brown PJ, Pappano WN, Sun C, Petros AM

ACS Med Chem Lett. 7(12):1102-1106. doi: 10.1021/acsmedchemlett.6b00303

Publication date: December 8, 2016

PMID: 27994746

Chemical probes and inhibitors of bromodomains outside the BET family.

Moustakim M, Clark PGK, Hay DA, Dixon DJ, Brennan PE

Medchemcomm. 7(12):2246-2264. doi: 10.1039/c6md00373g

Publication date: December 7, 2016

PMID: 29170712

Multivalent Histone and DNA Engagement by a PHD/BRD/PWWP Triple Reader Cassette Recruits ZMYND8 to K14ac-Rich Chromatin.

Savitsky P, Krojer T, Fujisawa T, Lambert JP, Picaud S, Wang CY, Shanle EK, Krajewski K, Friedrichsen H, Kanapin A, Goding C, Schapira M, Samsonova A, Strahl BD, Gingras AC, Filippakopoulos P

Cell Rep. 17(10):2724-2737. doi: 10.1016/j.celrep.2016.11.014

Publication date: December 6, 2016

PMID: 27926874

Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24.

Mehmood S, Marcoux J, Gault J, Quigley A, Michaelis S, Young SG, Carpenter EP, Robinson CV

Nat Chem. 8(12):1152-1158. doi: 10.1038/nchem.2591

Publication date: November 23, 2016

PMID: 27874871

Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair.

Vaz B, Popovic M, Newman JA, Fielden J, Aitkenhead H, Halder S, Singh AN, Vendrell I, Fischer R, Torrecilla I, Drobnitzky N, Freire R, Amor DJ, Lockhart PJ, Kessler BM, McKenna GW, Gileadi O, Ramadan K

Mol. Cell. 64(4):704-719. doi: 10.1016/j.molcel.2016.09.032

Publication date: November 17, 2016

PMID: 27871366

Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP.

Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, Ratnayaka I, Sullivan A, Brown NR, Endicott J, Knapp S, Kessler BM, Middleton MR, Siebold C, Jones EY, Sviderskaya EV, Cebon J, John T, Caballero OL, Goding CR, Lu X

Cancer Cell. 30(5):822-823. doi: 10.1016/j.ccell.2016.09.019

Publication date: November 14, 2016

PMID: 27846394

Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket.

Forster M, Chaikuad A, Bauer SM, Holstein J, Robers MB, Corona CR, Gehringer M, Pfaffenrot E, Ghoreschi K, Knapp S, Laufer SA

Cell Chem Biol. doi: 10.1016/j.chembiol.2016.10.008

Publication date: November 7, 2016

PMID: 27840070

Selective silencing of α-globin by the histone demethylase inhibitor IOX1: A potentially new pathway for treatment of β-thalassemia.

Mettananda S, Fisher CA, Sloane-Stanley JA, Taylor S, Oppermann U, Gibbons RJ, Higgs DR

Haematologica. doi: 10.3324/haematol.2016.155655

Publication date: November 3, 2016

PMID: 27810991

Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.

Butler KV, Ma A, Yu W, Li F, Tempel W, Babault N, Pittella-Silva F, Shao J, Wang J, Luo M, Vedadi M, Brown PJ, Arrowsmith CH, Jin J

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b01244

Publication date: November 2, 2016

PMID: 27804297

Structural insights into Gemin5-guided selection of pre-snRNAs for snRNP assembly.

Xu C, Ishikawa H, Izumikawa K, Li L, He H, Nobe Y, Yamauchi Y, Shahjee HM, Wu XH, Yu YT, Isobe T, Takahashi N, Min J

Genes Dev.. 30(21):2376-2390. doi: 10.1101/gad.288340.116

Publication date: November 1, 2016

PMID: 27881600

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.

Nakazawa Hewitt S, Dranow DM, Horst BG, Abendroth JA, Forte B, Hallyburton I, Jansen C, Baragana B, Choi R, Rivas KL, Hulverson MA, Dumais M, Edwards TE, Lorimer DD, Fairlamb AH, Gray DW, Read KD, Lehane AM, Kirk K, Myler PJ, Wernimont A, Walpole CS, Stacy R, Barrett LK, Gilbert IH, Van Voorhis WC

ACS Infect Dis. doi: 10.1021/acsinfecdis.6b00078

Publication date: October 31, 2016

PMID: 27798837

Characterizing Plexin GTPase Interactions Using Gel Filtration, Surface Plasmon Resonance Spectrometry, and Isothermal Titration Calorimetry.

Muller-Greven J, Kim S, Hota PK, Tong Y, Borthakur S, Buck M

Methods Mol. Biol.. 1493:89-105. doi: 10.1007/978-1-4939-6448-2_6

Publication date: October 28, 2016

PMID: 27787844

Development of chemical probes for the bromodomains of BRD7 and BRD9.

Clark PG, Dixon DJ, Brennan PE

Drug Discov Today Technol. 19:73-80. doi: 10.1016/j.ddtec.2016.05.002

Publication date: October 23, 2016

PMID: 27769361

Solution NMR structure of the HLTF HIRAN domain: a conserved module in SWI2/SNF2 DNA damage tolerance proteins.

Korzhnev DM, Neculai D, Dhe-Paganon S, Arrowsmith CH, Bezsonova I

J. Biomol. NMR. doi: 10.1007/s10858-016-0070-9

Publication date: October 22, 2016

PMID: 27771863

An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-specificity Tyrosine Phosphorylation-Regulated Kinases.

Chaikuad A, Diharce J, Schröder M, Foucourt A, Leblond B, Casagrande AS, Desire L, Bonnet P, Knapp S, Besson T

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b01083

Publication date: October 21, 2016

PMID: 27766861

Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.

Picaud S, Leonards K, Lambert JP, Dovey O, Wells C, Fedorov O, Monteiro O, Fujisawa T, Wang CY, Lingard H, Tallant C, Nikbin N, Guetzoyan L, Ingham R, Ley SV, Brennan P, Muller S, Samsonova A, Gingras AC, Schwaller J, Vassiliou G, Knapp S, Filippakopoulos P

Sci Adv. 2(10):e1600760. doi: 10.1126/sciadv.1600760

Publication date: October 21, 2016

PMID: 27757418

The substrate binding domains of human SIAH E3 ubiquitin ligases are now crystal clear.

Zhang Q, Wang Z, Hou F, Harding R, Huang X, Dong A, Walker JR, Tong Y

Biochim. Biophys. Acta. doi: 10.1016/j.bbagen.2016.10.019

Publication date: October 21, 2016

PMID: 27776223

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization.

Gebel J, Luh LM, Coutandin D, Osterburg C, Löhr F, Schäfer B, Frombach AS, Sumyk M, Buchner L, Krojer T, Salah E, Mathea S, Güntert P, Knapp S, Dötsch V

Cell Death Differ.. doi: 10.1038/cdd.2016.83

Publication date: October 7, 2016

PMID: 27716744

Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors.

Popp TA, Tallant C, Rogers C, Fedorov O, Brennan PE, Müller S, Knapp S, Bracher F

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b00774

Publication date: September 27, 2016

PMID: 27673482

The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway.

Carbonneau M, M Gagné L, Lalonde ME, Germain MA, Motorina A, Guiot MC, Secco B, Vincent EE, Tumber A, Hulea L, Bergeman J, Oppermann U, Jones RG, Laplante M, Topisirovic I, Petrecca K, Huot MÉ, Mallette FA

Nat Commun. 7:12700. doi: 10.1038/ncomms12700

Publication date: September 15, 2016

PMID: 27624942

Discovery and optimization of a selective ligand for the Switch/Sucrose Non-Fermenting-related bromodomains of Polybromo protein-1 by the use of virtual screening and hydration analysis.

Myrianthopoulos V, Gaboriaud-Kolar N, Tallant C, Hall ML, Grigoriou S, Brownlee PM, Fedorov O, Rogers C, Heidenreich D, Wanior M, Drosos N, Mexia N, Savitsky P, Bagratuni T, Kastritis E, Terpos E, Filippakopoulos P, Müller S, Skaltsounis AL, Downs JA, Knapp S, Mikros E

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b00355

Publication date: September 12, 2016

PMID: 27617704

Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due to Trapping of the Product.

Hughes SJ, Barnard L, Mottaghi K, Tempel W, Antoshchenko T, Hong BS, Allali-Hassani A, Smil D, Vedadi M, Strauss E, Park HW

ACS Infect Dis. 2(9):627-641. doi: 10.1021/acsinfecdis.6b00090

Publication date: September 9, 2016

PMID: 27759386

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1.

Harrison JS, Cornett EM, Goldfarb D, DaRosa PA, Li ZM, Yan F, Dickson BM, Guo AH, Cantu DV, Kaustov L, Brown PJ, Arrowsmith CH, Erie DA, Major MB, Klevit RE, Krajewski K, Kuhlman B, Strahl BD, Rothbart SB

Elife. 5:. doi: 10.7554/eLife.17101

Publication date: September 7, 2016

PMID: 27595565

Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.

Reid ES, Papandreou A, Drury S, Boustred C, Yue WW, Wedatilake Y, Beesley C, Jacques TS, Anderson G, Abulhoul L, Broomfield A, Cleary M, Grunewald S, Varadkar SM, Lench N, Rahman S, Gissen P, Clayton PT, Mills PB

Brain. doi: 10.1093/brain/aww221

Publication date: September 6, 2016

PMID: 27604308

A proposal for validation of antibodies.

Uhlen M, Bandrowski A, Carr S, Edwards A, Ellenberg J, Lundberg E, Rimm DL, Rodriguez H, Hiltke T, Snyder M, Yamamoto T

Nat. Methods. doi: 10.1038/nmeth.3995

Publication date: September 5, 2016

PMID: 27595404

Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

Shen Y, Szewczyk MM, Eram MS, Smil D, Kaniskan HÜ, de Freitas RF, Senisterra G, Li F, Schapira M, Brown PJ, Arrowsmith CH, Barsyte-Lovejoy D, Liu J, Vedadi M, Jin J

J. Med. Chem.. doi: 10.1021/acs.jmedchem.6b01033

Publication date: September 1, 2016

PMID: 27584694