Publications | Structural Genomics Consortium

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.

Ong HW, Yang X, Smith JL, Dickmander RJ, Brown JW, Havener TM, Taft-Benz S, Howell S, Sanders MK, Capener JL, Couñago RM, Chang E, Krämer A, Moorman NJ, Heise M, Axtman AD, Drewry DH, Willson TM

J Med Chem. doi: 10.1021/acs.jmedchem.4c00962

Publication date: July 3, 2024

PMID: 38959455

A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7.

Muñoz Sosa CJ, Lenz C, Hamann A, Farges F, Dopfer J, Krämer A, Cherkashyna V, Tarnovskiy A, Moroz YS, Proschak E, Němec V, Müller S, Saxena K, Knapp S

ACS Chem Biol. doi: 10.1021/acschembio.4c00301

Publication date: June 27, 2024

PMID: 38934237

Identification of Dihydropyrazolo[1,5-a]pyrazin-4(5H)-ones as Cyclic Products of β-Amidomethyl Vinyl Sulfone Alphavirus Cysteine Protease Inhibitors.

Ghoshal A, Magalhães ÁF, Asressu KH, Hossain MA, Todd MH, Willson TM

Pharmaceuticals (Basel). 17(7):. doi: 10.3390/ph17070836

Publication date: June 26, 2024

PMID: 39065687

Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.

Eguida M, Bret G, Sindt F, Li F, Chau I, Ackloo S, Arrowsmith C, Bolotokova A, Ghiabi P, Gibson E, Halabelian L, Houliston S, Harding RJ, Hutchinson A, Loppnau P, Perveen S, Seitova A, Zeng H, Schapira M, Rognan D

J Chem Inf Model. doi: 10.1021/acs.jcim.4c00601

Publication date: June 25, 2024

PMID: 38916159

A designed ankyrin-repeat protein that targets Parkinson's disease-associated LRRK2.

Dederer V, Sanz Murillo M, Karasmanis EP, Hatch KS, Chatterjee D, Preuss F, Abdul Azeez KR, Vu Nguyen L, Galicia C, Dreier B, Plückthun A, Versees W, Mathea S, Leschziner AE, Reck-Peterson SL, Knapp S

J Biol Chem. 107469. doi: 10.1016/j.jbc.2024.107469

Publication date: June 12, 2024

PMID: 38876305

Structural basis of p53 inactivation by cavity-creating cancer mutations and its implications for the development of mutant p53 reactivators.

Balourdas DI, Markl AM, Krämer A, Settanni G, Joerger AC

Cell Death Dis. 15(6):408. doi: 10.1038/s41419-024-06739-x

Publication date: June 11, 2024

PMID: 38862470

The Pan-Canadian Chemical Library: A Mechanism to Open Academic Chemistry to High-Throughput Virtual Screening.

Bedart C, Shimokura G, West FG, Wood TE, Batey RA, Irwin JJ, Schapira M

Sci Data. 11(1):597. doi: 10.1038/s41597-024-03443-5

Publication date: June 6, 2024

PMID: 38844472

Anti-FHL1 autoantibodies in adult patients with myositis: a longitudinal follow-up analysis.

Galindo-Feria AS, Lodin K, Horuluoglu B, Sarrafzadeh-Zargar S, Wigren E, Gräslund S, Danielsson O, Wahren-Herlenius M, Dastmalchi M, Lundberg IE

Rheumatology (Oxford). doi: 10.1093/rheumatology/keae317

Publication date: June 4, 2024

PMID: 38833674

Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.

de Souza Gama FH, Dutra LA, Hawgood M, Dos Reis CV, Serafim RAM, Ferreira MA, Teodoro BVM, Takarada JE, Santiago AS, Balourdas DI, Nilsson AS, Urien B, Almeida VM, Gileadi C, Ramos PZ, Salmazo A, Vasconcelos SNS, Cunha MR, Mueller S, Knapp S, Massirer KB, Elkins JM, Gileadi O, Mascarello A, Lemmens BBLG, Guimarães CRW, Azevedo H, Couñago RM

J Med Chem. doi: 10.1021/acs.jmedchem.3c02250

Publication date: May 23, 2024

PMID: 38780468

Splice variants of CK1α and CK1α-like: Comparative analysis of subcellular localization, kinase activity and function in the Wnt signaling pathway.

Gybeľ T, Čada Š, Klementová D, Schwalm MP, Berger BT, Šebesta M, Knapp S, Bryja V

J Biol Chem. 107407. doi: 10.1016/j.jbc.2024.107407

Publication date: May 23, 2024

PMID: 38796065

Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.

Chi G, Jaślan D, Kudrina V, Böck J, Li H, Pike ACW, Rautenberg S, Krogsaeter E, Bohstedt T, Wang D, McKinley G, Fernandez-Cid A, Mukhopadhyay SMM, Burgess-Brown NA, Keller M, Bracher F, Grimm C, Dürr KL

Structure. doi: 10.1016/j.str.2024.05.005

Publication date: May 23, 2024

PMID: 38815576

A chemical probe to modulate human GID4 Pro/N-degron interactions.

Owens DDG, Maitland MER, Khalili Yazdi A, Song X, Reber V, Schwalm MP, Machado RAC, Bauer N, Wang X, Szewczyk MM, Dong C, Dong A, Loppnau P, Calabrese MF, Dowling MS, Lee J, Montgomery JI, O'Connell TN, Subramanyam C, Wang F, Adamson EC, Schapira M, Gstaiger M, Knapp S, Vedadi M, Min J, Lajoie GA, Barsyte-Lovejoy D, Owen DR, Schild-Poulter C, Arrowsmith CH

Nat Chem Biol. doi: 10.1038/s41589-024-01618-0

Publication date: May 21, 2024

PMID: 38773330

STOPLIGHT: A Hit Scoring Calculator.

Wellnitz J, Martin HJ, Anwar Hossain M, Rath M, Fox C, Popov KI, Willson TM, Muratov EN, Tropsha A

J Chem Inf Model. doi: 10.1021/acs.jcim.4c00412

Publication date: May 20, 2024

PMID: 38768560

Development of Peptide Displacement Assays to Screen for Antagonists of DDB1 Interactions.

Yong D, Ahmad S, Mabanglo MF, Halabelian L, Schapira M, Ackloo S, Perveen S, Ghiabi P, Vedadi M

Biochemistry. doi: 10.1021/acs.biochem.4c00044

Publication date: May 10, 2024

PMID: 38729622

Probing the CRL4DCAF12 interactions with MAGEA3 and CCT5 di-Glu C-terminal degrons.

Righetto GL, Yin Y, Duda DM, Vu V, Szewczyk MM, Zeng H, Li Y, Loppnau P, Mei T, Li YY, Seitova A, Patrick AN, Brazeau JF, Chaudhry C, Barsyte-Lovejoy D, Santhakumar V, Halabelian L

PNAS Nexus. 3(4):pgae153. doi: 10.1093/pnasnexus/pgae153

Publication date: April 26, 2024

PMID: 38665159

Luciferase- and HaloTag-based reporter assays to measure small-molecule-induced degradation pathway in living cells.

Schwalm MP, Saxena K, Müller S, Knapp S

Nat Protoc. doi: 10.1038/s41596-024-00979-z

Publication date: April 18, 2024

PMID: 38637703

Expanding the ligand spaces for E3 ligases for the design of protein degraders.

Shah Zaib Saleem R, Schwalm MP, Knapp S

Bioorg Med Chem. 105:117718. doi: 10.1016/j.bmc.2024.117718

Publication date: April 12, 2024

PMID: 38621319

Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles.

Schwarz M, Kurkunov M, Wittlinger F, Rudalska R, Wang G, Schwalm MP, Rasch A, Wagner B, Laufer SA, Knapp S, Dauch D, Gehringer M

J Med Chem. doi: 10.1021/acs.jmedchem.3c02483

Publication date: April 11, 2024

PMID: 38604131

Emerging structure-based computational methods to screen the exploding accessible chemical space.

Bedart C, Simoben CV, Schapira M

Curr Opin Struct Biol. 86:102812. doi: 10.1016/j.sbi.2024.102812

Publication date: April 10, 2024

PMID: 38603987

MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.

Eldeeb MA, Fallahi A, Soumbasis A, Bayne AN, Trempe JF, Fon EA

Autophagy. doi: 10.1080/15548627.2024.2340399

Publication date: April 10, 2024

PMID: 38597070

Tetrahydropyridine LIMK inhibitors: Structure activity studies and biological characterization.

Champiré A, Berabez R, Braka A, Cosson A, Corret J, Girardin C, Serrano A, Aci-Sèche S, Bonnet P, Josselin B, Brindeau P, Ruchaud S, Leguevel R, Chatterjee D, Mathea S, Knapp S, Brion R, Verrecchia F, Vallée B, Plé K, Bénédetti H, Routier S

Eur J Med Chem. 271:116391. doi: 10.1016/j.ejmech.2024.116391

Publication date: April 9, 2024

PMID: 38669909

Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships.

Asquith CRM, East MP, Laitinen T, Alamillo-Ferrer C, Hartikainen E, Wells CI, Axtman AD, Drewry DH, Tizzard GJ, Poso A, Willson TM, Johnson GL

Eur J Med Chem. 271:116357. doi: 10.1016/j.ejmech.2024.116357

Publication date: April 2, 2024

PMID: 38636130

Identification and structural characterization of small molecule inhibitors of PINK1.

Rasool S, Shomali T, Truong L, Croteau N, Veyron S, Bustillos BA, Springer W, Fiesel FC, Trempe JF

Sci Rep. 14(1):7739. doi: 10.1038/s41598-024-58285-3

Publication date: April 2, 2024

PMID: 38565869

Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing.

Shen L, Ma X, Wang Y, Wang Z, Zhang Y, Pham HQH, Tao X, Cui Y, Wei J, Lin D, Abeywanada T, Hardikar S, Halabelian L, Smith N, Chen T, Barsyte-Lovejoy D, Qiu S, Xing Y, Yang Y

Nat Commun. 15(1):2809. doi: 10.1038/s41467-024-47107-9

Publication date: April 1, 2024

PMID: 38561334

Probing the CRL4DCAF12 interactions with MAGEA3 and CCT5 di-Glu C-terminal degrons.

Righetto GL, Yin Y, Duda DM, Vu V, Szewczyk MM, Zeng H, Li Y, Loppnau P, Mei T, Li YY, Seitova A, Patrick AN, Brazeau JF, Chaudhry C, Barsyte-Lovejoy D, Santhakumar V, Halabelian L

PNAS Nexus. 3(4):pgae153. doi: 10.1093/pnasnexus/pgae153

Publication date: April 1, 2024

PMID: 38665159

Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor.

Xiong Y, Greschik H, Johansson C, Seifert L, Gamble V, Park KS, Fagan V, Li F, Chau I, Vedadi M, Arrowsmith CH, Brennan P, Fedorov O, Jung M, Farnie G, Liu J, Oppermann U, Schüle R, Jin J

J Med Chem. doi: 10.1021/acs.jmedchem.4c00121

Publication date: March 27, 2024

PMID: 38533580

Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex.

Yazdi AK, Perveen S, Dong C, Song X, Dong A, Szewczyk MM, Calabrese MF, Casimiro-Garcia A, Chakrapani S, Dowling MS, Ficici E, Lee J, Montgomery JI, O'Connell TN, Skrzypek GJ, Tran TP, Troutman MD, Wang F, Young JA, Min J, Barsyte-Lovejoy D, Brown PJ, Santhakumar V, Arrowsmith CH, Vedadi M, Owen DR

RSC Med Chem. 15(3):1066-1071. doi: 10.1039/d3md00633f

Publication date: March 20, 2024

PMID: 38516600

Discovery of Conformationally Constrained ALK2 Inhibitors.

González-Álvarez H, Ensan D, Xin T, Wong JF, Zepeda-Velázquez CA, Cros J, Hoffer L, Kiyota T, Wilson BJ, Aman A, Roberts O, Isaac MB, Bullock AN, Smil D, Al-Awar R

J Med Chem. doi: 10.1021/acs.jmedchem.3c02308

Publication date: March 18, 2024

PMID: 38498998

Structure-guided drug discovery: back to the future.

Arrowsmith CH

Nat Struct Mol Biol. 31(3):395-396. doi: 10.1038/s41594-024-01244-3

Publication date: March 15, 2024

PMID: 38486110

Discovery of the sEH Inhibitor Epoxykynin as a Potent Kynurenine Pathway Modulator.

Dötsch L, Davies C, Hennes E, Schönfeld J, Kumar A, Guita CDCL, Ehrler JHM, Hiesinger K, Thavam S, Janning P, Sievers S, Knapp S, Proschak E, Ziegler S, Waldmann H

J Med Chem. doi: 10.1021/acs.jmedchem.3c02245

Publication date: March 12, 2024

PMID: 38470246

Big data and benchmarking initiatives to bridge the gap from AlphaFold to drug design.

Schapira M, Halabelian L, Arrowsmith CH, Harding RJ

Nat Chem Biol. doi: 10.1038/s41589-024-01570-z

Publication date: March 8, 2024

PMID: 38459278

Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.

Eldeeb MA, Bayne AN, Fallahi A, Goiran T, MacDougall EJ, Soumbasis A, Zorca CE, Tabah JJ, Thomas RA, Karpilovsky N, Mathur M, Durcan TM, Trempe JF, Fon EA

Proc Natl Acad Sci U S A. 121(10):e2313540121. doi: 10.1073/pnas.2313540121

Publication date: March 5, 2024

PMID: 38416681

Structure-guided drug discovery: back to the future.

Arrowsmith CH

Nat Struct Mol Biol. 31(3):395-396. doi: 10.1038/s41594-024-01244-3

Publication date: March 1, 2024

PMID: 38486110

Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors.

Rak M, Menge A, Tesch R, Berger LM, Balourdas DI, Shevchenko E, Krämer A, Elson L, Berger BT, Abdi I, Wahl LM, Poso A, Kaiser A, Hanke T, Kronenberger T, Joerger AC, Müller S, Knapp S

J Med Chem. doi: 10.1021/acs.jmedchem.3c02217

Publication date: February 29, 2024

PMID: 38422480

Synthesis of 5-Benzylamino and 5-Alkylamino-Substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity.

Asressu KH, Smith JL, Dickmander RJ, Moorman NJ, Wellnitz J, Popov KI, Axtman AD, Willson TM

Pharmaceuticals (Basel). 17(3):. doi: 10.3390/ph17030306

Publication date: February 27, 2024

PMID: 38543092

Kinetic characterization of human mRNA guanine-N7 methyltransferase.

Perveen S, Yazdi AK, Hajian T, Li F, Vedadi M

Sci Rep. 14(1):4509. doi: 10.1038/s41598-024-55184-5

Publication date: February 24, 2024

PMID: 38402266

Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.

Gilleran JA, Ashraf K, Delvillar M, Eck T, Fondekar R, Miller EB, Hutchinson A, Dong A, Seitova A, De Souza ML, Augeri D, Halabelian L, Siekierka J, Rotella DP, Gordon J, Childers WE, Grier MC, Staker BL, Roberge JY, Bhanot P

J Med Chem. doi: 10.1021/acs.jmedchem.3c01795

Publication date: February 19, 2024

PMID: 38372781

Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity.

Gerninghaus J, Zhubi R, Kraemer A, Karim M, Tran DHN, Joerger AC, Schreiber C, Berger LM, Berger BT, Ehret TAL, Elson L, Lenz C, Saxena K, Mueller S, Einav S, Knapp S, Hanke T

bioRxiv. doi: 10.1101/2024.02.18.580805

Publication date: February 18, 2024

PMID: 38405908

Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch.

Balzulat A, Zhu WF, Flauaus C, Hernandez-Olmos V, Heering J, Sethumadhavan S, Dubiel M, Frank A, Menge A, Hebchen M, Metzner K, Lu R, Lukowski R, Ruth P, Knapp S, Müller S, Steinhilber D, Hänelt I, Stark H, Proschak E, Schmidtko A

Adv Sci (Weinh). e2307237. doi: 10.1002/advs.202307237

Publication date: February 13, 2024

PMID: 38350720

Photosensitization enables Pauson-Khand-type reactions with nitrenes.

Li F, Zhu WF, Empel C, Datsenko O, Kumar A, Xu Y, Ehrler JHM, Atodiresei I, Knapp S, Mykhailiuk PK, Proschak E, Koenigs RM

Science. 383(6682):498-503. doi: 10.1126/science.adm8095

Publication date: February 2, 2024

PMID: 38301027

Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization.

Bauer N, Balourdas DI, Schneider JR, Zhang X, Berger LM, Berger BT, Schwalm MP, Klopp NA, Siveke JT, Knapp S, Joerger AC

ACS Chem Biol. doi: 10.1021/acschembio.3c00427

Publication date: January 31, 2024

PMID: 38291964

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Xie SC, Wang Y, Morton CJ, Metcalfe RD, Dogovski C, Pasaje CFA, Dunn E, Luth MR, Kumpornsin K, Istvan ES, Park JS, Fairhurst KJ, Ketprasit N, Yeo T, Yildirim O, Bhebhe MN, Klug DM, Rutledge PJ, Godoy LC, Dey S, De Souza ML, Siqueira-Neto JL, Du Y, Puhalovich T, Amini M, Shami G, Loesbanluechai D, Nie S, Williamson N, Jana GP, Maity BC, Thomson P, Foley T, Tan DS, Niles JC, Han BW, Goldberg DE, Burrows J, Fidock DA, Lee MCS, Winzeler EA, Griffin MDW, Todd MH, Tilley L

Nat Commun. 15(1):937. doi: 10.1038/s41467-024-45224-z

Publication date: January 31, 2024

PMID: 38297033

ChemRAP uncovers specific mRNA translation regulation via RNA 5' phospho-methylation.

Ipas H, Gouws EB, Abell NS, Chiou PC, Devanathan SK, Hervé S, Lee S, Mercado M, Reinsborough C, Halabelian L, Arrowsmith CH, Xhemalçe B

EMBO Rep. doi: 10.1038/s44319-024-00059-z

Publication date: January 23, 2024

PMID: 38263329

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.

Mann MK, Wolf E, Silva M, Kwak HA, Wilson B, Bolotokova A, Wilson DJ, Harding RJ, Schapira M

ACS Omega. 9(1):917-924. doi: 10.1021/acsomega.3c07070

Publication date: January 9, 2024

PMID: 38222562

Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3.

Galal KA, Krämer A, Strickland BG, Smith JL, Dickmander RJ, Moorman NJ, Willson TM

Bioorg Med Chem Lett. 99:129617. doi: 10.1016/j.bmcl.2024.129617

Publication date: January 8, 2024

PMID: 38199328

Atg8 family proteins, LIR/AIM motifs and other interaction modes.

Rogov VV, Nezis IP, Tsapras P, Zhang H, Dagdas Y, Noda NN, Nakatogawa H, Wirth M, Mouilleron S, McEwan DG, Behrends C, Deretic V, Elazar Z, Tooze SA, Dikic I, Lamark T, Johansen T

Autophagy Rep. 2(1):. doi: 10.1080/27694127.2023.2188523

Publication date: December 31, 2023

PMID: 38214012

Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3.

Amrhein JA, Berger LM, Balourdas DI, Joerger AC, Menge A, KrÃ¤mer A, Frischkorn JM, Berger BT, Elson L, Kaiser A, Schubert-Zsilavecz M, MÃ¼ller S, Knapp S, Hanke T

J Med Chem. doi: 10.1021/acs.jmedchem.3c01980

Publication date: December 21, 2023

PMID: 38126712

Discovery of pyrazolo[3,4-d]pyrimidines as novel mitogen-activated protein kinase kinase 3 (MKK3) inhibitors.

Takarada JE, Cunha MR, Almeida VM, Vasconcelos SNS, Santiago AS, Godoi PH, Salmazo A, Ramos PZ, Fala AM, de Souza LR, Da Silva IEP, Bengtson MH, Massirer KB, CouÃ±ago RM

Bioorg Med Chem. 98:117561. doi: 10.1016/j.bmc.2023.117561

Publication date: December 20, 2023

PMID: 38157838

The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition.

Kimani SW, Perveen S, Szewezyk M, Zeng H, Dong A, Li F, Ghiabi P, Li Y, Chau I, Arrowsmith CH, Barsyte-Lovejoy D, Santhakumar V, Vedadi M, Halabelian L

Commun Biol. 6(1):1272. doi: 10.1038/s42003-023-05655-8

Publication date: December 16, 2023

PMID: 38104184

Characterization of 2,4-Dianilinopyrimidines Against Five P. falciparum Kinases PfARK1, PfARK3, PfNEK3, PfPK9, and PfPKB.

Ong HW, de Silva C, Avalani K, Kwarcinski F, Mansfield CR, Chirgwin M, Truong A, Derbyshire ER, Zutshi R, Drewry DH

ACS Med Chem Lett. 14(12):1774-1784. doi: 10.1021/acsmedchemlett.3c00354

Publication date: December 14, 2023

PMID: 38116430