Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?

Click chemistry is universally recognized as a powerful strategy for the fast and precise assembly of diverse building blocks. Targeted Protein Degradation (TPD) is a new therapeutic modality based on heterobifunctional small-molecule degraders that provides new opportunities to medicinal chemists dealing with undruggable targets and incurable diseases. Here, we highlight how very recently the TPD field and that of click chemistry have merged, opening up the possibility for fine-tuning the properties of a degrader, chemically assembled through a "click" synthesis. By reviewing concrete examples, we want to provide the reader with the insight that the application of click and bioorthogonal chemistry in the TDP field may be a winning combination.

[1]  A. Ciulli,et al.  Proximity-Based Modalities for Biology and Medicine , 2023, ACS central science.

[2]  Mingxing Teng,et al.  The rise of degrader drugs. , 2023, Cell chemical biology.

[3]  J Zhang,et al.  Discovery of intracellular self-assembly protein degraders driven by tumor-specific activatable bioorthogonal reaction. , 2023, European journal of medicinal chemistry.

[4]  H. Ran,et al.  Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death. , 2023, Journal of medicinal chemistry.

[5]  Zhengyu Jiang,et al.  Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation. , 2023, Journal of the American Chemical Society.

[6]  A. Milelli,et al.  Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery , 2022, ACS bio & med chem Au.

[7]  Yashu Liu,et al.  The sirtuin family in health and disease , 2022, Signal Transduction and Targeted Therapy.

[8]  Ying Tan,et al.  PROTAC Degrader of Estrogen Receptor α Targeting DNA-Binding Domain in Breast Cancer. , 2022, ACS pharmacology & translational science.

[9]  Hua-Li Qin,et al.  Chemical and biology of sulfur fluoride exchange (SuFEx) click chemistry for drug discovery. , 2022, Bioorganic chemistry.

[10]  R. Gomis,et al.  Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen. , 2022, European journal of medicinal chemistry.

[11]  A. Milelli,et al.  Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One , 2022, Journal of medicinal chemistry.

[12]  Guangdi Wang,et al.  Synthesis and biological evaluation of niclosamide PROTACs , 2022, Bioorganic & medicinal chemistry letters.

[13]  Lei Wang,et al.  Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors. , 2022, Journal of medicinal chemistry.

[14]  Tetsuro Kamiya.  Copper in the tumor microenvironment and tumor metastasis , 2022, Journal of clinical biochemistry and nutrition.

[15]  K. Matsuno,et al.  Development of Chimeric Molecules That Degrade the Estrogen Receptor Using Decoy Oligonucleotide Ligands. , 2021, ACS medicinal chemistry letters.

[16]  A. M. Habib,et al.  Emerging innate biological properties of nano-drug delivery systems: A focus on PAMAM dendrimers and their clinical potential. , 2021, Advanced drug delivery reviews.

[17]  Y. Seimbille,et al.  IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications , 2021, Molecules.

[18]  Xian Chen,et al.  TF-PROTACs Enable Targeted Degradation of Transcription Factors. , 2021, Journal of the American Chemical Society.

[19]  M. Ishikawa,et al.  In vivo synthetic chemistry of proteolysis targeting chimeras (PROTACs). , 2021, Bioorganic & medicinal chemistry.

[20]  A. Keefe,et al.  Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening. , 2021, Journal of medicinal chemistry.

[21]  Qiaojun He,et al.  Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy , 2021, Nature Chemical Biology.

[22]  Lixia Chen,et al.  Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP. , 2021, Journal of medicinal chemistry.

[23]  C. Bertozzi,et al.  LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation , 2021, Nature Chemical Biology.

[24]  C. Crews,et al.  Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs , 2021, The Journal of biological chemistry.

[25]  D. Wolan,et al.  Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia , 2020, bioRxiv.

[26]  Almaz Zagidullin,et al.  Novel approaches for the rational design of PROTAC linkers , 2020, Exploration of targeted anti-tumor therapy.

[27]  F. Feng,et al.  PROTACs suppression of GSK-3β, a crucial kinase in neurodegenerative diseases. , 2020, European journal of medicinal chemistry.

[28]  Aldrin V. Vasco,et al.  Isonitriles: Versatile Handles for the Bioorthogonal Functionalization of Proteins , 2020, ACS omega.

[29]  Chad E. Townsend,et al.  Understanding and Improving the Membrane Permeability of VH032-Based PROTACs , 2020, ACS medicinal chemistry letters.

[30]  I. Navarro-Teulon,et al.  Optimization of IEDDA bioorthogonal system: Efficient process to improve trans-cyclooctene/tetrazine interaction. , 2020, European journal of medicinal chemistry.

[31]  Nan Bai,et al.  Rationalizing PROTAC-mediated ternary complex formation using Rosetta , 2020, bioRxiv.

[32]  U. Schepers,et al.  The Staudinger Ligation. , 2020, Chemical reviews.

[33]  V. Nizet,et al.  SuFEx-Enabled High-Throughput Medicinal Chemistry , 2019 .

[34]  T. Akaike,et al.  AUTACs: Cargo-Specific Degraders Using Selective Autophagy. , 2019, Molecular cell.

[35]  V. Krchňák,et al.  Traceless Solid-Phase Organic Synthesis. , 2019, Chemical reviews.

[36]  K. Sharpless,et al.  Modular click chemistry libraries for functional screens using a diazotizing reagent , 2019, Nature.

[37]  J. Bushweller.  Targeting transcription factors in cancer — from undruggable to reality , 2019, Nature Reviews Cancer.

[38]  S. Chandarlapaty,et al.  Potent and Preferential Degradation of CDK6 via PROteolysis TArgeting Chimera Degraders. , 2019, Journal of medicinal chemistry.

[39]  H. Aisa,et al.  1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview , 2019, Bioorganic & Medicinal Chemistry.

[40]  Weiping Tang,et al.  Development of Multi-Functional Histone Deacetylase 6 Degraders with Potent Anti-Myeloma Activity. , 2019, Journal of medicinal chemistry.

[41]  Bin Yang,et al.  Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges. , 2019, Bioorganic & medicinal chemistry letters.

[42]  Brian J. Levandowski,et al.  Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles. , 2019, Angewandte Chemie.

[43]  Peng Zhan,et al.  Recent applications of click chemistry in drug discovery , 2019, Expert opinion on drug discovery.

[44]  B. Jiang,et al.  Chemoselective Synthesis of Lenalidomide-Based PROTAC Library Using Alkylation Reaction. , 2019, Organic letters.

[45]  A. Ciulli,et al.  SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate , 2019, ACS chemical biology.

[46]  Hua-Li Qin,et al.  Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review , 2018, European Journal of Medicinal Chemistry.

[47]  Weiping Tang,et al.  Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. , 2018, Bioorganic & medicinal chemistry letters.

[48]  Neal K. Devaraj,et al.  The Future of Bioorthogonal Chemistry , 2018, ACS central science.

[49]  K. Sharpless,et al.  A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt Emerging as an "F-SO2 +" Donor of Unprecedented Reactivity, Selectivity, and Scope. , 2018, Angewandte Chemie.

[50]  Peng Wu,et al.  SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization. , 2018, Journal of the American Chemical Society.

[51]  T. Hughes,et al.  The Human Transcription Factors , 2018, Cell.

[52]  C. Crews,et al.  Small-Molecule Modulation of Protein Homeostasis. , 2017, Chemical reviews.

[53]  J. Ovádi,et al.  Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals). , 2017, Journal of medicinal chemistry.

[54]  J. McCarter,et al.  A "Click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation. , 2017, Journal of medicinal chemistry.

[55]  Jan Kihlberg,et al.  How Big Is Too Big for Cell Permeability? , 2017, Journal of medicinal chemistry.

[56]  D. Lamont,et al.  Structural basis of PROTAC cooperative recognition for selective protein degradation , 2017, Nature chemical biology.

[57]  T. Heightman,et al.  Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras , 2016, ACS central science.

[58]  Neville E. Sanjana,et al.  Transcription control by the ENL YEATS domain in acute leukemia , 2016, Nature.

[59]  Craig M. Crews,et al.  Induced protein degradation: an emerging drug discovery paradigm , 2016, Nature Reviews Drug Discovery.

[60]  K. Sharpless,et al.  A Heck-Matsuda Process for the Synthesis of β-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry. , 2016, Angewandte Chemie.

[61]  S. Schreiber,et al.  Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma , 2016, Proceedings of the National Academy of Sciences.

[62]  Xiufeng Pang,et al.  Linifanib (ABT-869) Potentiates the Efficacy of Chemotherapeutic Agents through the Suppression of Receptor Tyrosine Kinase-Mediated AKT/mTOR Signaling Pathways in Gastric Cancer , 2016, Scientific Reports.

[63]  Eunhwa Ko,et al.  Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. , 2016, Angewandte Chemie.

[64]  Xiaoyan Pan,et al.  Discovery of novel VEGFR-2 inhibitors. Part 5: Exploration of diverse hinge-binding fragments via core-refining approach. , 2015, European journal of medicinal chemistry.

[65]  James E. Bradner,et al.  Phthalimide conjugation as a strategy for in vivo target protein degradation , 2015, Science.

[66]  A. Ciulli,et al.  Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4 , 2015, ACS chemical biology.

[67]  J. Macor,et al.  Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core. , 2015, Bioorganic & medicinal chemistry letters.

[68]  Wolfgang Sippl,et al.  Selective Sirt2 inhibition by ligand-induced rearrangement of the active site , 2015, Nature Communications.

[69]  Younan Xia,et al.  Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry. , 2014, Angewandte Chemie.

[70]  Jianping Xie,et al.  From aggregation-induced emission of Au(I)-thiolate complexes to ultrabright Au(0)@Au(I)-thiolate core-shell nanoclusters. , 2012, Journal of the American Chemical Society.

[71]  Jingli Hou,et al.  The impact of click chemistry in medicinal chemistry , 2012, Expert opinion on drug discovery.

[72]  Thomas B. Sundberg,et al.  Identification of Hydrophobic Tags for the Degradation of Stabilized Proteins , 2012, Chembiochem : a European journal of chemical biology.

[73]  C. Bertozzi,et al.  From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions , 2011, Accounts of chemical research.

[74]  T. Corson,et al.  Small-Molecule Hydrophobic Tagging Induced Degradation of HaloTag Fusion Proteins , 2011, Nature Chemical Biology.

[75]  William B. Smith,et al.  Selective inhibition of BET bromodomains , 2010, Nature.

[76]  C. Bertozzi,et al.  Cu-free click cycloaddition reactions in chemical biology. , 2010, Chemical Society reviews.

[77]  Christopher N Bowman,et al.  Thiol-ene click chemistry. , 2010, Angewandte Chemie.

[78]  Baoguang Zhao,et al.  Design, synthesis and selection of DNA-encoded small-molecule libraries. , 2009, Nature chemical biology.

[79]  T. Corson,et al.  Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One. , 2008, ACS chemical biology.

[80]  Joseph M. Fox,et al.  Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity. , 2008, Journal of the American Chemical Society.

[81]  Morten Meldal,et al.  Cu-catalyzed azide-alkyne cycloaddition. , 2008, Chemical reviews.

[82]  C. Boyault,et al.  HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination , 2007, Oncogene.

[83]  M. Finn,et al.  Mechanism of the ligand-free CuI-catalyzed azide-alkyne cycloaddition reaction. , 2005, Angewandte Chemie.

[84]  Jennifer A. Prescher,et al.  A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. , 2004, Journal of the American Chemical Society.

[85]  Morten Meldal,et al.  Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. , 2002, The Journal of organic chemistry.

[86]  Carolyn R Bertozzi,et al.  Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[87]  C. Klinge.  Estrogen receptor interaction with estrogen response elements. , 2001, Nucleic acids research.

[88]  B. Wayburn,et al.  Design, synthesis, and pharmacological characterization of 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a high-affinity nonsteroidal androgen receptor ligand. , 2000, Journal of medicinal chemistry.

[89]  C. Bertozzi,et al.  Cell surface engineering by a modified Staudinger reaction. , 2000, Science.

[90]  W. Binder,et al.  The CuAAC: Principles, Homogeneous and Heterogeneous Catalysts, and Novel Developments and Applications. , 2019, Macromolecular rapid communications.

[91]  C. Crews.  Inducing Protein Degradation as a Therapeutic Strategy. , 2018, Journal of medicinal chemistry.