Advances in sulfonyl exchange chemical biology: expanding druggable target space

Lyn H. Jones

Chem. Sci., 2025, 16, 10119
DOI: 10.1039/D5SC02647D

Sulfur(vi) fluorides as tools in biomolecular and medicinal chemistry

Sabrina N. Carneiro, Samuel R. Khasnavis, Jisun Lee, Todd W. Butler, Jaimeen D. Majmudar, Christopher W. am Ende and Nicholas D. Ball

Org. Biomol. Chem., 2023, 21, 1356
DOI: 10.1039/D2OB01891H

Synthetic modification of protein surfaces to mediate induced-proximity pharmacology

Lyn H. Jones

RSC Med. Chem., 2024, 15, 2974
DOI: 10.1039/D4MD00388H

Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead

Radosław P. Nowak, Leah Ragosta, Fidel Huerta, Hu Liu, Scott B. Ficarro, Justin T. Cruite, Rebecca J. Metivier, Katherine A. Donovan, Jarrod A. Marto, Eric S. Fischer, Breanna L. Zerfas and Lyn H. Jones

RSC Chem. Biol., 2023, 4, 906
DOI: 10.1039/D3CB00103B

Applications of covalent chemistry in targeted protein degradation

Dong Lu, Xin Yu, Hanfeng Lin, Ran Cheng, Erika Y. Monroy, Xiaoli Qi, Meng C. Wang and Jin Wang

Chem. Soc. Rev., 2022, 51, 9243
DOI: 10.1039/D2CS00362G

A twist in the tale: shifting from covalent targeting of a tyrosine in JAK3 to a lysine in MK2

Laura Hillebrand, Guiqun Wang, Alexander Rasch, Benedikt Masberg, Apirat Chaikuad, Thales Kronenberger, Ellen Günther, Michael Forster, Antti Poso, Michael Lämmerhofer, Stefan A. Laufer, Stefan Knapp and Matthias Gehringer

RSC Med. Chem., 2025
DOI: 10.1039/D5MD00440C

Covalent drugs targeting histidine – an unexploited opportunity?

Jianwei Che and Lyn H. Jones

RSC Med. Chem., 2022, 13, 1121
DOI: 10.1039/D2MD00258B

Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives

Radosław P. Nowak, Jianwei Che, Silas Ferrao, Nikki R. Kong, Hu Liu, Breanna L. Zerfas and Lyn H. Jones

RSC Med. Chem., 2023, 14, 501
DOI: 10.1039/D2MD00347C

Proximity-induced SuFEx increases the potency of cytosolic nucleotidase inhibitors and reveals a rare example of covalently targeted histidine

Mikolaj Chrominski, Marcin Warminski, Mateusz Kozarski, Dorota Kubacka, Joanna Panecka-Hofman, Tomasz Spiewla, Mikolaj Zmudzinski, Jacek Jemeility and Joanna Kowalska

RSC Chem. Biol., 2025, 6, 942
DOI: 10.1039/D5CB00005J

Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators

Yingpeng Liu, Radosław P. Nowak, Jianwei Che, Katherine A. Donovan, Fidel Huerta, Hu Liu, Rebecca J. Metivier, Eric S. Fischer and Lyn H. Jones

RSC Med. Chem., 2024, 15, 607
DOI: 10.1039/D3MD00652B

Chemical tools for probing histidine modifications

Nurgül Bilgin, Jordi C. J. Hintzen and Jasmin Mecinović

Chem. Commun., 2025, 61, 3805
DOI: 10.1039/D4CC06586G

Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions

Yang Gao, Baishan Jiang, Hellen Kim, Matthew J. Berberich, Jianwei Che, Katherine A. Donovan, John M. Hatcher, Fidel Huerta, Nicholas P. Kwiatkowski, Yingpeng Liu, Peter P. Liuni, Rebecca J. Metivier, Vineeth K. Murali, Radosław P. Nowak, Tinghu Zhang, Eric S. Fischer, Nathanael S. Gray and Lyn H. Jones

J. Med. Chem., 2023, 66, 5524
DOI: 10.1021/acs.jmedchem.2c01864

Covalent fragment approaches targeting non-cysteine residues

Noémi Csorba, Péter Ábrányi-Balogh and György M. Keserű

Trends in Pharmacological Sciences, 2023, 44, 802
DOI: 10.1016/j.tips.2023.08.014

Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios

Alyssa L. Verano, Inchul You, Katherine A. Donovan, Nada Mageed, Hong Yue, Radosław P. Nowak, Eric S. Fischer, Eric S. Wang and Nathanael S. Gray

ACS Chem. Biol., 2022, 17, 2404
DOI: 10.1021/acschembio.2c00439

Advances in Activity‐Based Protein Profiling of Functional Tyrosines in Proteomes

Jeffrey W. Brulet, Anthony M. Ciancone, Kun Yuan and Ku‐Lung Hsu

Israel Journal of Chemistry, 2023, 63
DOI: 10.1002/ijch.202300001

Leveraging Covalency to Stabilize Ternary Complex Formation For Cell–Cell “Induced Proximity”

Karolina Krygier, Anjalee N. Wijetunge, Arthur Srayeddin, Harrison Mccann and Anthony F. Rullo

ACS Chem. Biol., 2024, 19, 2103
DOI: 10.1021/acschembio.4c00286

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Aivaras Vaškevičius, Denis Baronas, Janis Leitans, Agnė Kvietkauskaitė, Audronė Rukšėnaitė, Elena Manakova, Zigmantas Toleikis, Algirdas Kaupinis, Andris Kazaks, Marius Gedgaudas, Aurelija Mickevičiūtė, Vaida Juozapaitienė, Helgi B Schiöth, Kristaps Jaudzems, Mindaugas Valius, Kaspars Tars, Saulius Gražulis, Franz-Josef Meyer-Almes, Jurgita Matulienė, Asta Zubrienė, Virginija Dudutienė and Daumantas Matulis

eLife, 2024, 13
DOI: 10.7554/eLife.101401.3

Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome

Katharine E. Gilbert, Aini Vuorinen, Arron Aatkar, Peter Pogány, Jonathan Pettinger, Emma K. Grant, Joanna M. Kirkpatrick, Katrin Rittinger, David House, Glenn A. Burley and Jacob T. Bush

ACS Chem. Biol., 2023, 18, 285
DOI: 10.1021/acschembio.2c00633

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang and Lyn H. Jones

Expert Opinion on Drug Discovery, 2023, 18, 725
DOI: 10.1080/17460441.2023.2218642

Advancing Covalent Ligand and Drug Discovery beyond Cysteine

Gibae Kim, R. Justin Grams and Ku-Lung Hsu

Chem. Rev., 2025, 125, 6653
DOI: 10.1021/acs.chemrev.5c00001

Unconventional reactivity of sulfonyl fluorides

Juan J. Rojas and James A. Bull

Trends in Chemistry, 2025, 7, 124
DOI: 10.1016/j.trechm.2025.01.003

Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl-1 BH3 Mimetics

Giulia Alboreggia, Parima Udompholkul, Emma L. Atienza, Kendall Muzzarelli, Zahra Assar and Maurizio Pellecchia

J. Med. Chem., 2024, 67, 20214
DOI: 10.1021/acs.jmedchem.4c01541

Unleashing the Power of Covalent Drugs for Protein Degradation

Meng‐Jie Fu, Hang Jin, Shao‐Peng Wang, Liang Shen, Hong‐Min Liu, Ying Liu, Yi‐Chao Zheng and Xing‐Jie Dai

Medicinal Research Reviews, 2025, 45, 1045
DOI: 10.1002/med.22101

Histidine-Covalent Stapled Alpha-Helical Peptides Targeting hMcl-1

Giulia Alboreggia, Parima Udompholkul, Carlo Baggio, Kendall Muzzarelli, Zahra Assar and Maurizio Pellecchia

J. Med. Chem., 2024, 67, 8172
DOI: 10.1021/acs.jmedchem.4c00277

Targeted Covalent Modification Strategies for Drugging the Undruggable Targets

Tomonori Tamura, Masaharu Kawano and Itaru Hamachi

Chem. Rev., 2025, 125, 1191
DOI: 10.1021/acs.chemrev.4c00745

Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes

Ying Chen, Gregory B. Craven, Roarke A. Kamber, Adolfo Cuesta, Serhii Zhersh, Yurii S. Moroz, Michael C. Bassik and Jack Taunton

Nat. Chem., 2023, 15, 1616
DOI: 10.1038/s41557-023-01281-3

Sulfur fluoride exchange

Joshua A. Homer, Long Xu, Namitharan Kayambu, Qinheng Zheng, Eun Joung Choi, Byeong Moon Kim, K. Barry Sharpless, Han Zuilhof, Jiajia Dong and John E. Moses

Nat Rev Methods Primers, 2023, 3
DOI: 10.1038/s43586-023-00241-y

Identification of an Allene Warhead That Selectively Targets a Histidine Residue in the Escherichia coli Oxidoreductase Enzyme DsbA

Yildiz Tasdan, Gautham R. Balaji, Naureen Akhtar, Olga Ilyichova, Taylor Cunliffe, Begoña Heras, Loic Le Strat, James Murray, Ben Capuano, Martin J. Scanlon and Bradley C. Doak

ACS Med. Chem. Lett., 2025, 16, 625
DOI: 10.1021/acsmedchemlett.5c00016

Property-Based Optimization of Cereblon-Based Molecular Glue Degraders

Lyn H. Jones

ACS Med. Chem. Lett., 2025, 16, 1456
DOI: 10.1021/acsmedchemlett.5c00308

Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D

Qinheng Zheng, Ziyang Zhang, Keelan Z. Guiley and Kevan M. Shokat

Nat Chem Biol, 2024, 20, 1114
DOI: 10.1038/s41589-024-01565-w

Activity-based protein profiling in drug/pesticide discovery: Recent advances in target identification of antibacterial compounds

Kunlun Chen, Ling Zhang, Yue Ding, Zhaoju Sun, Jiao Meng, Rongshuang Luo, Xiang Zhou, Liwei Liu and Song Yang

Bioorganic Chemistry, 2024, 151, 107655
DOI: 10.1016/j.bioorg.2024.107655

Covalent Proximity Inducers

Nir London

Chem. Rev., 2025, 125, 326
DOI: 10.1021/acs.chemrev.4c00570

Covalent Bifunctional Molecules (CBMs): Achievements and Challenges

Yuting Xin, Fangsu Chen, Qidong You, Lei Wang and Qiuyue Zhang

Medicinal Research Reviews, 2025
DOI: 10.1002/med.70011

Targeted protein degradation in cancers: Orthodox PROTACs and beyond

Jin Li, Xinxin Chen, Aiping Lu and Chao Liang

The Innovation, 2023, 4, 100413
DOI: 10.1016/j.xinn.2023.100413

Covalent Stapling of the Cereblon Sensor Loop Histidine Using Sulfur-Heterocycle Exchange

Justin T. Cruite, Radosław P. Nowak, Katherine A. Donovan, Scott B. Ficarro, Huang Huang, Hu Liu, Yingpeng Liu, Jarrod A. Marto, Rebecca J. Metivier, Eric S. Fischer and Lyn H. Jones

ACS Med. Chem. Lett., 2023, 14, 1576
DOI: 10.1021/acsmedchemlett.3c00371

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Laura Hillebrand, Xiaojun Julia Liang, Ricardo A. M. Serafim and Matthias Gehringer

J. Med. Chem., 2024, 67, 7668
DOI: 10.1021/acs.jmedchem.3c01825

CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

Riya Thapa, Asif Ahmad Bhat, Gaurav Gupta, S. Renuka Jyothi, Irwanjot Kaur, Sachin Kumar, Naveen Sharma, G. V. Siva Prasad, Atreyi Pramanik and Haider Ali

Chem Biol Drug Des, 2024, 104
DOI: 10.1111/cbdd.70009

Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments

Arron Aatkar, Aini Vuorinen, Oliver E. Longfield, Katharine Gilbert, Rachel Peltier-Heap, Craig D. Wagner, Francesca Zappacosta, Katrin Rittinger, Chun-wa Chung, David House, Nicholas C. O. Tomkinson and Jacob T. Bush

ACS Chem. Biol., 2023, 18, 1926
DOI: 10.1021/acschembio.3c00034

Research progress on covalent inhibitors targeting alkaline amino acids

Bing Zhao, Sha Xu, Shiqing Zhou, Xiangru Jiang, Ailin Jiang, Hongrui Lei and Xin Zhai

Bioorganic Chemistry, 2025, 163, 108800
DOI: 10.1016/j.bioorg.2025.108800

Development of covalent inhibitors: Principle, design, and application in cancer

Lang Zheng, Yang Li, Defa Wu, Huan Xiao, Shilong Zheng, Guan Wang and Qiu Sun

MedComm – Oncology, 2023, 2
DOI: 10.1002/mog2.56

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Aivaras Vaškevičius, Denis Baronas, Janis Leitans, Agnė Kvietkauskaitė, Audronė Rukšėnaitė, Elena Manakova, Zigmantas Toleikis, Algirdas Kaupinis, Andris Kazaks, Marius Gedgaudas, Aurelija Mickevičiūtė, Vaida Juozapaitienė, Helgi B Schiöth, Kristaps Jaudzems, Mindaugas Valius, Kaspars Tars, Saulius Gražulis, Franz-Josef Meyer-Almes, Jurgita Matulienė, Asta Zubrienė, Virginija Dudutienė and Daumantas Matulis

eLife, 2024, 13
DOI: 10.7554/eLife.101401

Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs

Rishi R. Shah, Elena De Vita, Preethi S. Sathyamurthi, Daniel Conole, Xinyue Zhang, Elliot Fellows, Eleanor R. Dickinson, Carlos M. Fleites, Markus A. Queisser, John D. Harling and Edward W. Tate

J. Med. Chem., 2024, 67, 4641
DOI: 10.1021/acs.jmedchem.3c02123