Emerging modes-of-action in drug discovery

Eric Valeur, Frank Narjes, Christian Ottmann and Alleyn T. Plowright

Med. Chem. Commun., 2019, 10, 1550
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Selective degradation-inducing probes for studying cereblon (CRBN) biology

Chelsea E. Powell, Guangyan Du, Jonathan W. Bushman, Zhixiang He, Tinghu Zhang, Eric S. Fischer and Nathanael S. Gray

RSC Med. Chem., 2021, 12, 1381
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PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

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Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

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E3 ligase ligand chemistries: from building blocks to protein degraders

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Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Christian Steinebach, Yuen Lam Dora Ng, Izidor Sosič, Chih-Shia Lee, Sirui Chen, Stefanie Lindner, Lan Phuong Vu, Aleša Bricelj, Reza Haschemi, Marius Monschke, Elisabeth Steinwarz, Karl G. Wagner, Gerd Bendas, Ji Luo, Michael Gütschow and Jan Krönke

Chem. Sci., 2020, 11, 3474
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Encoding BRAF inhibitor functions in protein degraders

Daniel S. J. Miller, Sabine A. Voell, Izidor Sosič, Matic Proj, Olivia W. Rossanese, Gregor Schnakenburg, Michael Gütschow, Ian Collins and Christian Steinebach

RSC Med. Chem., 2022, 13, 731
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Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders

Claudia J. Diehl and Alessio Ciulli

Chem. Soc. Rev., 2022, 51, 8216
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Developing degraders: principles and perspectives on design and chemical space

Hannah J. Maple, Nat Clayden, Anne Baron, Callum Stacey and Robert Felix

Med. Chem. Commun., 2019, 10, 1755
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A MedChem toolbox for cereblon-directed PROTACs

Christian Steinebach, Izidor Sosič, Stefanie Lindner, Aleša Bricelj, Franziska Kohl, Yuen Lam Dora Ng, Marius Monschke, Karl G. Wagner, Jan Krönke and Michael Gütschow

Med. Chem. Commun., 2019, 10, 1037
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Development of the first non-hydroxamate selective HDAC6 degraders

Tim Keuler, Beate König, Nico Bückreiß, Fabian B. Kraft, Philipp König, Linda Schäker-Hübner, Christian Steinebach, Gerd Bendas, Michael Gütschow and Finn K. Hansen

Chem. Commun., 2022, 58, 11087
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Preclinical Studies of PROTACs in Hematological Malignancies

Ota Fuchs and Radka Bokorova

CHDDT, 2021, 21, 7
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Sunitinib-based Proteolysis Targeting Chimeras (PROTACs) reduced the protein levels of FLT-3 and c-KIT in leukemia cell lines

Jiadai Zhai, Chuang Li, Bingxia Sun, Sinan Wang, Yuting Cui, Qingzhi Gao and Feng Sang

Bioorganic & Medicinal Chemistry Letters, 2022, 78, 129041
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Acetyl-CoA Carboxylase Proteolysis-Targeting Chimeras: Conceptual Design and Application as Insecticides

Qi Xu, Hao Feng, Zhong Li and Xusheng Shao

J. Agric. Food Chem., 2024, 72, 18809
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Design and characterization of a heterobifunctional degrader of KEAP1

Hao Chen, Nghi H. Nguyen, Charlene M. Magtoto, Simon A. Cobbold, Grace M. Bidgood, Lizeth G. Meza Guzman, Lachlan W. Richardson, Jason Corbin, Amanda E. Au, Bernhard C. Lechtenberg, Rebecca Feltham, Kate D. Sutherland, Christoph Grohmann, Sandra E. Nicholson and Brad E. Sleebs

Redox Biology, 2023, 59, 102552
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Targeted Degradation of the Estrogen Receptor α through Unconventional Coactivator Binding Site (CBS)

Yubo Wang, Baohua Xie, Xiaofei Deng, Chune Dong and Hai-Bing Zhou

J. Med. Chem., 2025, 68, 13640
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Rational Design and Synthesis of HSF1-PROTACs for Anticancer Drug Development

Chiranjeev Sharma, Myeong A Choi, Yoojin Song and Young Ho Seo

Molecules, 2022, 27, 1655
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Targeted Protein Degradation: Clinical Advances in the Field of Oncology

Abdelrahman K. A. A. Salama, Marija V. Trkulja, Emilio Casanova and Iris Z. Uras

IJMS, 2022, 23, 15440
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Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera

Kidae Kim, Dong Ho Lee, Sungryul Park, Seung-Hyun Jo, Bonsu Ku, Sung Goo Park, Byoung Chul Park, Yeong Uk Jeon, Sunjoo Ahn, Chung Hyo Kang, Daehee Hwang, Sehyun Chae, Jae Du Ha, Sunhong Kim, Jong Yeon Hwang and Jeong-Hoon Kim

Sci Rep, 2019, 9
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Degraders early developability assessment: face-to-face with molecular properties

Giuseppe Ermondi, Maura Vallaro and Giulia Caron

Drug Discovery Today, 2020, 25, 1585
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On the correlation of cereblon binding, fluorination and antiangiogenic properties of immunomodulatory drugs

Christopher Heim, Samuel Maiwald, Christian Steinebach, Matthew K. Collins, Jonathan Strope, Cindy H. Chau, William D. Figg, Michael Gütschow and Marcus D. Hartmann

Biochemical and Biophysical Research Communications, 2021, 534, 67
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Leveraging Dual-Ligase Recruitment to Enhance Protein Degradation via a Heterotrivalent Proteolysis Targeting Chimera

Adam G. Bond, Miquel Muñoz i Ordoño, Celia M. Bisbach, Conner Craigon, Nikolai Makukhin, Elizabeth A. Caine, Manjula Nagala, Marjeta Urh, Georg E. Winter, Kristin M. Riching and Alessio Ciulli

J. Am. Chem. Soc., 2024, 146, 33675
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Strategies for designing proteolysis targeting chimaeras (PROTACs)

Shipeng He, Guoqiang Dong, Junfei Cheng, Ying Wu and Chunquan Sheng

Medicinal Research Reviews, 2022, 42, 1280
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Bifunctional robots inducing targeted protein degradation

M Elizabeth Sobhia, Harish Kumar and Sonia Kumari

European Journal of Medicinal Chemistry, 2023, 255, 115384
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Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models

Lukas M. Gockel, Vladlena Pfeifer, Fabian Baltes, Rafael D. Bachmaier, Karl G. Wagner, Gerd Bendas, Michael Gütschow, Izidor Sosič and Christian Steinebach

Archiv der Pharmazie, 2022, 355
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Sweet and Blind Spots in E3 Ligase Ligand Space Revealed by a Thermophoresis-Based Assay

Samuel Maiwald, Christopher Heim, Birte Hernandez Alvarez and Marcus D. Hartmann

ACS Med. Chem. Lett., 2021, 12, 74
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Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation

Yanran Li, Kaiwen Bao, Jiyue Sun, Ruixin Ge, Qiqing Zhang, Bing Zhang, Xiaojie Yan, Junlin Li, Fengying Shi, Meiling Zhang, Jinzhi Zang, Min Liu, Jun Zhou, Wenyi Mi, Songbo Xie, Dongxing Chen, Lei Shi and Cheng Dong

Nat Struct Mol Biol, 2025
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Discovery of pan-IAP degraders via a CRBN recruiting mechanism

Seulki Park, Dayoung Kim, Woori Lee, Jin Hwa Cho, Sungyoung Kim, Ga Seul Lee, Jeong Hee Moon, Jung-Ae Kim, Jae Du Ha, Jeong-Hoon Kim and Hyun Jin Kim

European Journal of Medicinal Chemistry, 2023, 245, 114910
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Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly

Vishnu Balaji and Thorsten Hoppe

F1000Res, 2020, 9, 88
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PROTACs– a game-changing technology

Markella Konstantinidou, Jingyao Li, Bidong Zhang, Zefeng Wang, Shabnam Shaabani, Frans Ter Brake, Khaled Essa and Alexander Dömling

Expert Opinion on Drug Discovery, 2019, 14, 1255
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Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability

Hao Wu, Jeremy Murray, Noriko Ishisoko, Alexandra Frommlet, Gauri Deshmukh, Antonio DiPasquale, Melinda M. Mulvihill, Donglu Zhang, John G. Quinn, Robert A. Blake, Wayne J. Fairbrother and Jakob Fuhrmann

J. Med. Chem., 2024, 67, 8585
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Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma

Saeko Kuwahara‐Ota, Yuji Shimura, Christian Steinebach, Reiko Isa, Junko Yamaguchi, Daichi Nishiyama, Yuto Fujibayashi, Tomoko Takimoto‐Shimomura, Yoshimi Mizuno, Yayoi Matsumura‐Kimoto, Taku Tsukamoto, Yoshiaki Chinen, Tsutomu Kobayashi, Shigeo Horiike, Masafumi Taniwaki, Michael Gütschow and Junya Kuroda

Br J Haematol, 2020, 191, 784
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Frontiers in Medicinal Chemistry 2022 Goes Virtual

Eleonora Diamanti, María Méndez, Tatjana Ross, Christian A. Kuttruff, Julien Lefranc, Franca‐Maria Klingler, Franz von Nussbaum, Manfred Jung and Matthias Gehringer

ChemMedChem, 2022, 17
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Design and linkage optimization of ursane-thalidomide-based PROTACs and identification of their targeted-degradation properties to MDM2 protein

Zhiwen Qi, Guliang Yang, Tao Deng, Jianmin Wang, Hao Zhou, Sergey A. Popov, Elvira E. Shults and Chengzhang Wang

Bioorganic Chemistry, 2021, 111, 104901
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Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation

Aimo Kannt and Ivan Đikić

Cell Chemical Biology, 2021, 28, 1014
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Central Nervous System Targeted Protein Degraders

Bedwyr ab Ion Thomas, H. Lois Lewis, D. Heulyn Jones and Simon E. Ward

Biomolecules, 2023, 13, 1164
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Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues

Marta Pichlak, Tomasz Sobierajski, Katarzyna M. Błażewska and Edyta Gendaszewska-Darmach

Journal of Enzyme Inhibition and Medicinal Chemistry, 2023, 38
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De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives

Christopher Heim, Dimanthi Pliatsika, Farnoush Mousavizadeh, Kerstin Bär, Birte Hernandez Alvarez, Athanassios Giannis and Marcus D. Hartmann

J. Med. Chem., 2019, 62, 6615
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Bifunctional chemical probes inducing protein–protein interactions

Chiara Maniaci and Alessio Ciulli

Current Opinion in Chemical Biology, 2019, 52, 145
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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Ming He, Chaoguo Cao, Zhihao Ni, Yongbo Liu, Peilu Song, Shuang Hao, Yuna He, Xiuyun Sun and Yu Rao

Sig Transduct Target Ther, 2022, 7
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ELIOT: A platform to navigate the E3 pocketome and aid the design of new PROTACs

Tommaso Palomba, Massimo Baroni, Simon Cross, Gabriele Cruciani and Lydia Siragusa

Chem Biol Drug Des, 2023, 101, 69
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AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss

Santanu Hati, Marisa Zallocchi, Robert Hazlitt, Yuju Li, Sarath Vijayakumar, Jaeki Min, Zoran Rankovic, Sándor Lovas and Jian Zuo

European Journal of Medicinal Chemistry, 2021, 226, 113849
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High-resolution structures of the bound effectors avadomide (CC-122) and iberdomide (CC-220) highlight advantages and limitations of the MsCI4 soaking system

Christopher Heim and Marcus D. Hartmann

Acta Crystallogr D Struct Biol, 2022, 78, 290
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Targeted protein degradation: elements of PROTAC design

Stacey-Lynn Paiva and Craig M Crews

Current Opinion in Chemical Biology, 2019, 50, 111
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Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications

Laura Goracci, Jenny Desantis, Aurora Valeri, Beatrice Castellani, Michela Eleuteri and Gabriele Cruciani

J. Med. Chem., 2020, 63, 11615
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Update on targeted cancer therapies, single or in combination, and their fine tuning for precision medicine

Sara S Bashraheel, Alexander Domling and Sayed K Goda

Biomedicine & Pharmacotherapy, 2020, 125, 110009
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Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation

Jianyu Yan, Tengfei Li, Zhenyuan Miao, Pei Wang, Chunquan Sheng and Chunlin Zhuang

J. Med. Chem., 2022, 65, 8798
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PROTACs: A novel strategy for cancer therapy

Jing Liu, Jia Ma, Yi Liu, Jun Xia, Yuyun Li, Z. Peter Wang and Wenyi Wei

Seminars in Cancer Biology, 2020, 67, 171
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Current strategies for the design of PROTAC linkers: a critical review

Robert I. Troup, Charlene Fallan and Matthias G. J. Baud

Exploration of Targeted Anti-tumor Therapy, 2020, 1
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Advancing brain tumor therapy: unveiling the potential of PROTACs for targeted protein degradation

Saooda Ibrahim, Muhammad Umer Khan, Saadia Noreen, Safia Firdous, Iqra Khurram, Raima Rehman, Muhammad Arshad Javed and Qurban Ali

Cytotechnology, 2025, 77
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Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins

Yuen Lam Dora Ng, Aleša Bricelj, Jacqueline A. Jansen, Arunima Murgai, Kirsten Peter, Katherine A. Donovan, Michael Gütschow, Jan Krönke, Christian Steinebach and Izidor Sosič

J. Med. Chem., 2023, 66, 4703
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Research Progress of PROTAC-Degraded CDKs in the Treatment of Breast Cancer

Kexin Zhao, Jun Zhang, Zhe Yang, Rong Wang, Yuhuan Shi, Yanan Ji, Shengjun Zhang and Minli Liu

BCTT, 2025, Volume 17, 511
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Reaction of Diisobutylaluminum Borohydride, a Binary Hydride, with Selected Organic Compounds Containing Representative Functional Groups

Gabriella Amberchan, Rachel A. Snelling, Enrique Moya, Madison Landi, Kyle Lutz, Roxanne Gatihi and Bakthan Singaram

J. Org. Chem., 2021, 86, 6207
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Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Miriam Girardini, Chiara Maniaci, Scott J. Hughes, Andrea Testa and Alessio Ciulli

Bioorganic & Medicinal Chemistry, 2019, 27, 2466
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PROTACs: great opportunities for academia and industry

Xiuyun Sun, Hongying Gao, Yiqing Yang, Ming He, Yue Wu, Yugang Song, Yan Tong and Yu Rao

Sig Transduct Target Ther, 2019, 4
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Proteolytic Targeting Chimeras with Specificity for Plasma Membrane and Intracellular Estrogen Receptors

Anh S. Lu, Milad Rouhimoghadam, Christopher K. Arnatt, Edward J. Filardo and Aliasger K. Salem

Mol. Pharmaceutics, 2021, 18, 1455
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Discovery of novel BTK PROTACs for B-Cell lymphomas

Yunpeng Zhao, Yongzhi Shu, Jun Lin, Zhendong Chen, Qiong Xie, Yanning Bao, Lixue Lu, Nannan Sun and Yonghui Wang

European Journal of Medicinal Chemistry, 2021, 225, 113820
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Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway

Fengqin Wang, Ying Zhan, Manman Li, Lidan Wang, Austin Zheng, Changbai Liu, Hu Wang and Tao Wang

ACS Pharmacol. Transl. Sci., 2023, 6, 76
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Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

Troy A. Bemis, James J. La Clair and Michael D. Burkart

J. Med. Chem., 2021, 64, 8042
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Harnessing the Power of Proteolysis for Targeted Protein Inactivation

Rati Verma, Dane Mohl and Raymond J. Deshaies

Molecular Cell, 2020, 77, 446
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Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase

Anastasia A. Sachkova, Daria V. Andreeva, Alexander S. Tikhomirov, Alexander M. Scherbakov, Diana I. Salnikova, Danila V. Sorokin, Fedor B. Bogdanov, Yulia D. Rysina, Andrey E. Shchekotikhin, Ekaterina S. Shchegravina and Alexey Yu. Fedorov

Pharmaceutics, 2022, 14, 2829
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E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

Tasuku Ishida and Alessio Ciulli

SLAS Discovery, 2021, 26, 484
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A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

Irene Preet Bhela, Alice Ranza, Federica Carolina Balestrero, Marta Serafini, Silvio Aprile, Rita Maria Concetta Di Martino, Fabrizio Condorelli and Tracey Pirali

J. Med. Chem., 2022, 65, 15282
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Exploring the target scope of KEAP1 E3 ligase-based PROTACs

Guangyan Du, Jie Jiang, Nathaniel J. Henning, Nozhat Safaee, Eriko Koide, Radosław P. Nowak, Katherine A. Donovan, Hojong Yoon, Inchul You, Hong Yue, Nicholas A. Eleuteri, Zhixiang He, Zhengnian Li, Hubert T. Huang, Jianwei Che, Behnam Nabet, Tinghu Zhang, Eric S. Fischer and Nathanael S. Gray

Cell Chemical Biology, 2022, 29, 1470
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Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

Laura Sinatra, Jing Yang, Julian Schliehe-Diecks, Niklas Dienstbier, Melina Vogt, Philip Gebing, Luisa M. Bachmann, Melf Sönnichsen, Thomas Lenz, Kai Stühler, Andrea Schöler, Arndt Borkhardt, Sanil Bhatia and Finn K. Hansen

J. Med. Chem., 2022, 65, 16860
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Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

Shipeng He, Junhui Ma, Yuxin Fang, Ying Liu, Shanchao Wu, Guoqiang Dong, Wei Wang and Chunquan Sheng

Acta Pharmaceutica Sinica B, 2021, 11, 1617
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Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

Christian Steinebach, Aleša Bricelj, Arunima Murgai, Izidor Sosič, Luca Bischof, Yuen Lam Dora Ng, Christopher Heim, Samuel Maiwald, Matic Proj, Rabea Voget, Felix Feller, Janez Košmrlj, Valeriia Sapozhnikova, Annika Schmidt, Maximilian Rudolf Zuleeg, Patricia Lemnitzer, Philipp Mertins, Finn K. Hansen, Michael Gütschow, Jan Krönke and Marcus D. Hartmann

J. Med. Chem., 2023, 66, 14513
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