Abstract
The development of bioactive small molecules as probes or drug candidates requires discovery platforms that enable access to chemical diversity and can quickly reveal new ligands for a target of interest. Within the past 15 years, DNA-encoded library (DEL) technology has matured into a widely used platform for small-molecule discovery, yielding a wide variety of bioactive ligands for many therapeutically relevant targets. DELs offer many advantages compared with traditional screening methods, including efficiency of screening, easily multiplexed targets and library selections, minimized resources needed to evaluate an entire DEL and large library sizes. This Review provides accounts of recently described small molecules discovered from DELs, including their initial identification, optimization and validation of biological properties including suitability for clinical applications.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Brenner, S. & Lerner, R. A. Encoded combinatorial chemistry. Proc. Natl Acad. Sci. USA 89, 5381–5383 (1992).
Clark, M. A. Selecting chemicals: the emerging utility of DNA-encoded libraries. Curr. Opin. Chem. Biol. 14, 396–403 (2010).
Kleiner, R. E., Dumelin, C. E. & Liu, D. R. Small-molecule discovery from DNA-encoded chemical libraries. Chem. Soc. Rev. 40, 5707–5717 (2011).
Gartner, Z. J. & Liu, D. R. The generality of DNA-templated synthesis as a basis for evolving non-natural small molecules. J. Am. Chem. Soc. 123, 6961–6963 (2001).
Tse, B. N., Snyder, T. M., Shen, Y. & Liu, D. R. Translation of DNA into a library of 13 000 synthetic small-molecule macrocycles suitable for in vitro selection. J. Am. Chem. Soc. 130, 15611–15626 (2008).
Hansen, M. H. et al. A yoctoliter-scale DNA reactor for small-molecule evolution. J. Am. Chem. Soc. 131, 1322–1327 (2009).
Wrenn, S. J., Weisinger, R. M., Halpin, D. R. & Harbury, P. B. Synthetic ligands discovered by in vitro selection. J. Am. Chem. Soc. 129, 13137–13143 (2007).
Clark, M. A. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 5, 647–654 (2009).
Melkko, S., Scheuermann, J., Dumelin, C. E. & Neri, D. Encoded self-assembling chemical libraries. Nat. Biotechnol. 22, 568–574 (2004).
Halpin, D. R. & Harbury, P. B. DNA display II. Genetic manipulation of combinatorial chemistry libraries for small-molecule evolution. PLoS Biol. 2, E174 (2004).
Buller, F. et al. Design and synthesis of a novel DNA-encoded chemical library using Diels–Alder cycloadditions. Bioorg. Med. Chem. Lett. 18, 5926–5931 (2008).
Doyon, J. B., Snyder, T. M. & Liu, D. R. Highly sensitive in vitro selections for DNA-linked synthetic small molecules with protein binding affinity and specificity. J. Am. Chem. Soc. 125, 12372–12373 (2003).
Mannocci, L. et al. High-throughput sequencing allows for the identification of binding molecules from DNA-encoded chemical libraries. Proc. Natl Acad. Sci. USA 105, 17670–17675 (2008).
Kleiner, R. E., Dumelin, C. E., Tiu, G. C., Sakurai, K. & Liu, D. R. In vitro selection of a DNA-templated small-molecule library reveals a class of macrocyclic kinase inhibitors. J. Am. Chem. Soc. 132, 11779–11791 (2010).
Sunkari, Y. K., Siripuram, V. K., Nguyen, T. L. & Flajolet, M. High-power screening (HPS) empowered by DNA-encoded libraries. Trends Pharmacol. Sci. 43, 4–15 (2022).
Castan, I. F. S. F., Graham, J. S., Salvini, C. L. A., Stanway-Gordon, H. A. & Waring, M. J. On the design of lead-like DNA-encoded chemical libraries. Bioorg. Med. Chem. 43, 116273 (2021).
Fitzgerald, P. R. & Paegel, B. M. DNA-encoded chemistry: drug discovery from a few good reactions. Chem. Rev. 121, 7155–7177 (2021).
Song, M. & Hwang, G. T. DNA-encoded library screening as core platform technology in drug discovery: its synthetic method development and applications in DEL synthesis. J. Med. Chem. 63, 6578–6599 (2020).
Dickson, P. & Kodadek, T. Chemical composition of DNA-encoded libraries, past present and future. Org. Biomol. Chem. 17, 4676–4688 (2019).
Gironda-Martínez, A., Donckele, E. J., Samain, F. & Neri, D. DNA-encoded chemical libraries: a comprehensive review with succesful stories and future challenges. ACS Pharmacol. Transl. Sci. 4, 1265–1279 (2021).
Kunig, V. B. K., Potowski, M., Klika Škopić, M. & Brunschweiger, A. Scanning protein surfaces with DNA-encoded libraries. ChemMedChem 16, 1048–1062 (2021).
Zhao, G., Huang, Y., Zhou, Y., Li, Y. & Li, X. Future challenges with DNA-encoded chemical libraries in the drug discovery domain. Expert Opin. Drug Discov. 14, 735–753 (2019).
Neri, D. & Lerner, R. A. DNA-encoded chemical libraries: a selection system based on endowing organic compounds with amplifiable information. Annu. Rev. Biochem. 87, 479–502 (2018).
Huang, Y., Li, Y. & Li, X. Strategies for developing DNA encoded libraries beyond binding assays. Nat. Chem. 14, 129–140 (2022).
Song, Y. & Li, X. Evolution of the selection methods of DNA-encoded chemical libraries. Acc. Chem. Res. 54, 3491–3503 (2021).
Huang, Y. & Li, X. Recent advances on the selection methods of DNA-encoded libraries. ChemBioChem 22, 2384–2397 (2021).
Kodadek, T., Paciaroni, N. G., Balzarini, M. & Dickson, P. Beyond protein binding: recent advances in screening DNA-encoded libraries. Chem. Commun. 55, 13330–13341 (2019).
Dawadi, S. et al. Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library. Proc. Natl Acad. Sci. USA 117, 16782–16789 (2020).
Gironda-Martínez, A. et al. Identification and validation of new interleukin-2 ligands using DNA-encoded libraries. J. Med. Chem. 64, 17496–17510 (2021).
Taylor, D. M. et al. Identifying oxacillinase-48 carbapenemase inhibitors using DNA-encoded chemical libraries. ACS Infect. Dis. 6, 1214–1227 (2020).
Steffek, M. et al. A multifaceted hit-finding approach reveals novel LC3 family ligands. Biochemistry 62, 633–644 (2023).
Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein–protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016).
Peterson, A. A. et al. Discovery and molecular basis of subtype-selective cyclophilin inhibitors. Nat. Chem. Biol. 18, 1184–1195 (2022).
Usanov, D. L., Chan, A. I., Maianti, J. P. & Liu, D. R. Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules. Nat. Chem. 10, 704–714 (2018).
Kunig, V. B. K. et al. TEAD–YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi peptidomimetics. Angew. Chem. Int. Ed. 59, 20338–20342 (2020).
Johannes, J. W. et al. Structure based design of non-natural peptidic macrocyclic Mcl-1 inhibitors. ACS Med. Chem. Lett. 8, 239–244 (2017).
Wellaway, C. R. et al. Discovery of a bromodomain and extraterminal inhibitor with a low predicted human dose through synergistic use of encoded library technology and fragment screening. J. Med. Chem. 63, 714–746 (2020).
Fernández-Montalván, A. E. et al. Isoform-selective ATAD2 chemical probe with novel chemical structure and unusual mode of action. ACS Chem. Biol. 12, 2730–2736 (2017).
Lomas, D. A. et al. Development of a small molecule that corrects misfolding and increases secretion of Z α1‐antitrypsin. EMBO Mol. Med. 13, e13167 (2021).
Yuen, L. H. et al. A focused DNA-encoded chemical library for the discovery of inhibitors of NAD+-dependent enzymes. J. Am. Chem. Soc. 141, 5169–5181 (2019).
Lemke, M. et al. Integrating DNA-encoded chemical libraries with virtual combinatorial library screening: optimizing a PARP10 inhibitor. Bioorg. Med. Chem. Lett. 30, 127464 (2020).
MacHutta, C. A. et al. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. Nat. Commun. 8, 16081 (2017).
Concha, N. et al. Discovery and characterization of a class of pyrazole inhibitors of bacterial undecaprenyl pyrophosphate synthase. J. Med. Chem. 59, 7299–7304 (2016).
Chamakuri, S. et al. DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors. Proc. Natl Acad. Sci. USA 118, 8–13 (2021).
Podolin, P. L. et al. In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. Prostaglandins Other Lipid Mediat. 104–105, 25–31 (2013).
Belyanskaya, S. L., Ding, Y., Callahan, J. F., Lazaar, A. L. & Israel, D. I. Discovering drugs with DNA-encoded library technology: from concept to clinic with an inhibitor of soluble epoxide hydrolase. ChemBioChem 18, 837–842 (2017).
Ding, Y. et al. Discovery of soluble epoxide hydrolase inhibitors through DNA-encoded library technology (ELT). Bioorg. Med. Chem. 41, 116216 (2021).
Ding, Y., Thalji, R. K. & Marino, J. P. J. Novel sEH inhibitors and their use. Patent WO2009049157A1 (2009).
Ottl, J., Leder, L., Schaefer, J. V. & Dumelin, C. E. Encoded library technologies as integrated lead finding platforms for drug discovery. Molecules 24, 1629 (2019).
Satz, A. L. What do you get from DNA-encoded libraries? ACS Med. Chem. Lett. 9, 408–410 (2018).
Arico-Muendel, C. C. From haystack to needle: finding value with DNA encoded library technology at GSK. MedChemComm 7, 1898–1909 (2016).
Lazaar, A. L., Baines, A., Ahmed, M., Boardley, R. & Hussaini, A. Inhibition of soluble epoxide hydrolase does not augment hypoxic pulmonary vasoconstriction in healthy subjects. Am. J. Respir. Crit. Care Med. 193, A6840 (2016).
Lazaar, A. L. et al. Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor. Br. J. Clin. Pharmacol. 81, 971–979 (2016).
Yang, L. et al. Mechanisms of vascular dysfunction in COPD and effects of a novel soluble epoxide hydrolase inhibitor in smokers. Chest 151, 555–563 (2017).
Martini, R. P. et al. A double-blind, randomized, placebo-controlled trial of soluble epoxide hydrolase inhibition in patients with aneurysmal subarachnoid hemorrhage. Neurocrit. Care 36, 905–915 (2022).
Luther, J. M. et al. GSK2256294 decreases sEH (soluble epoxide hydrolase) activity in plasma, muscle, and adipose and reduces F2-isoprostanes but does not alter insulin sensitivity in humans. Hypertension 78, 1092–1102 (2021).
Harris, P. A. et al. DNA-encoded library screening identifies benzo[b][1,4]oxazepin-4-ones as highly potent and monoselective receptor interacting protein 1 kinase inhibitors. J. Med. Chem. 59, 2163–2178 (2016).
Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
Weisel, K. et al. Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers. Pharmacol. Res. Perspect. 5, e00365 (2017).
Tompson, D. J. et al. Comparison of the pharmacokinetics of RIPK1 inhibitor GSK2982772 in healthy Western and Japanese subjects. Eur. J. Drug Metab. Pharmacokinet. 46, 71–83 (2020).
Tompson, D. J. et al. Development of a prototype, once-daily, modified-release formulation for the short half-life RIPK1 inhibitor GSK2982772. Pharm. Res. 38, 1235–1245 (2021).
Tompson, D. et al. Development of a once-daily modified-release formulation for the short half-life RIPK1 inhibitor GSK2982772 using DiffCORE technology. Pharm. Res. 39, 153–165 (2022).
Weisel, K. et al. Response to inhibition of receptor-interacting protein kinase 1 (RIPK1) in active plaque psoriasis: a randomized placebo-controlled study. Clin. Pharmacol. Ther. 108, 808–816 (2020).
Weisel, K. et al. A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis. Arthritis Res. Ther. 23, 85 (2021).
Weisel, K. et al. A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis. BMJ Open Gastroenterol. 8, e000680 (2021).
Xia, C. et al. Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors. Eur. J. Med. Chem. 220, 113484 (2021).
Yoshikawa, M. et al. Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c] pyridine derivatives as potent, orally available, and brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure-kinetic relationships. J. Med. Chem. 61, 2384–2409 (2018).
Wang, W. et al. RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell 34, 757–774.e7 (2018).
Harris, P. A. et al. Identification of a RIP1 kinase inhibitor clinical candidate (GSK3145095) for the treatment of pancreatic cancer. ACS Med. Chem. Lett. 10, 857–862 (2019).
Cuozzo, J. W. et al. Novel autotaxin inhibitor for the treatment of idiopathic pulmonary fibrosis: a clinical candidate discovered using DNA-encoded chemistry. J. Med. Chem. 63, 7840–7856 (2020).
Richter, H. et al. DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of Alport syndrome. ACS Chem. Biol. 14, 37–49 (2019).
Rianjongdee, F. et al. Discovery of a highly selective BET BD2 inhibitor from a DNA-encoded library technology screening hit. J. Med. Chem. 64, 10806–10833 (2021).
Disch, J. S. et al. Bispecific estrogen receptor α degraders incorporating novel binders identified using DNA-encoded chemical library screening. J. Med. Chem. 64, 5049–5066 (2021).
Veerman, J. J. N. et al. Discovery of 2,4-1 H-imidazole carboxamides as potent and selective TAK1 inhibitors. ACS Med. Chem. Lett. 12, 555–562 (2021).
Yu, Z. et al. Discovery and characterization of bromodomain 2-specific inhibitors of BRDT. Proc. Natl Acad. Sci. USA 118, e2021102118 (2021).
Lee, E. C. Y. et al. Discovery of novel, potent inhibitors of hydroxy acid oxidase 1 (HAO1) using DNA-encoded chemical library screening. J. Med. Chem. 64, 6730–6744 (2021).
Ryan, M. D. et al. Discovery of novel UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors with activity against Pseudomonas aeruginosa. J. Med. Chem. 64, 14377–14425 (2021).
Kung, P. P. et al. Characterization of specific N-α-acetyltransferase 50 (Naa50) inhibitors identified using a DNA encoded library. ACS Med. Chem. Lett. 11, 1175–1184 (2020).
Bassi, G. et al. A single-stranded DNA-encoded chemical library based on a stereoisomeric scaffold enables ligand discovery by modular assembly of building blocks. Adv. Sci. 7, 2001970 (2020).
Favalli, N. et al. Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications. Nat. Chem. 13, 540–548 (2021).
Bassi, G. et al. Specific inhibitor of placental alkaline phosphatase isolated from a DNA-encoded chemical library targets tumor of the female reproductive tract. J. Med. Chem. 64, 15799–15809 (2021).
Cuozzo, J. W. et al. Discovery of a potent BTK inhibitor with a novel binding mode by using parallel selections with a DNA-encoded chemical library. ChemBioChem 18, 864–871 (2017).
Guilinger, J. P. et al. Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry. Bioorg. Med. Chem. 42, 116223 (2021).
Nissink, J. W. M. et al. Generating selective leads for Mer kinase inhibitors — example of a comprehensive lead-generation strategy. J. Med. Chem. 64, 3165–3184 (2021).
McCoull, W. et al. Optimization of an Imidazo[1,2-a]pyridine series to afford highly selective type I1/2 dual Mer/Axl kinase inhibitors with in vivo efficacy. J. Med. Chem. 64, 13524–13539 (2021).
Brown, D. G. et al. Agonists and antagonists of protease-activated receptor 2 discovered within a DNA-encoded chemical library using mutational stabilization of the target. SLAS Discov. 23, 429–436 (2018).
Kennedy, A. J. et al. Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition. Commun. Biol. 3, 782 (2020).
Cheng, R. K. Y. et al. Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545, 112–115 (2017).
Carey, R. M. et al. Polarization of protease-activated receptor 2 (PAR-2) signaling is altered during airway epithelial remodeling and deciliation. J. Biol. Chem. 295, 6721–6740 (2020).
Huang, X. et al. Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis. Aging 11, 12532–12545 (2019).
Sun, L. et al. Protease-activated receptor 2 (PAR-2) antagonist AZ3451 mitigates oxidized low-density lipoprotein (Ox-LDL)-induced damage and endothelial inflammation. Chem. Res. Toxicol. 34, 2202–2208 (2021).
Ahn, S. et al. Allosteric ‘beta-blocker’ isolated from a DNA-encoded small molecule library. Proc. Natl Acad. Sci. USA 114, 1708–1713 (2017).
Liu, X. et al. Mechanism of intracellular allosteric β2 AR antagonist revealed by X-ray crystal structure. Nature 548, 480–484 (2017).
Ahn, S. et al. Small-molecule positive allosteric modulators of the β2-adrenoceptor isolated from DNA-encoded libraries. Mol. Pharmacol. 94, 850–861 (2018).
Liu, X. et al. Mechanism of β2AR regulation by an intracellular positive allosteric modulator. Science 364, 1283–1287 (2019).
Wang, J. et al. β-Arrestin–biased allosteric modulator potentiates carvedilol-stimulated β adrenergic receptor cardioprotection. Mol. Pharmacol. 100, 568–579 (2021).
Zhou, Y., Shen, W., Peng, J., Deng, Y. & Li, X. Identification of isoform/domain-selective fragments from the selection of DNA-encoded dynamic library. Bioorg. Med. Chem. 45, 116328 (2021).
Kim, D. et al. Application of a substrate-mediated selection with c-Src tyrosine kinase to a DNA-encoded chemical library. Molecules 24, 2764 (2019).
Litovchick, A. et al. Novel nucleic acid binding small molecules discovered using DNA-encoded chemistry. Molecules 24, 2026 (2019).
Denton, K. E. et al. Robustness of in vitro selection assays of DNA-encoded peptidomimetic ligands to CBX7 and CBX8. SLAS Discov. 23, 417–428 (2018).
Wang, S. et al. Optimization of ligands using focused DNA-encoded libraries to develop a selective, cell-permeable CBX8 chromodomain inhibitor. ACS Chem. Biol. 15, 112–131 (2020).
Wang, S. et al. A potent, selective CBX2 chromodomain ligand and its cellular activity during prostate cancer neuroendocrine differentiation. ChemBioChem 22, 2335–2344 (2021).
Wu, Z. et al. Cell-based selection expands the utility of DNA-encoded small-molecule library technology to cell surface drug targets: identification of novel antagonists of the NK3 tachykinin receptor. ACS Comb. Sci. 17, 722–731 (2015).
Cochrane, W. G., Fitzgerald, P. R. & Paegel, B. M. Antibacterial discovery via phenotypic DNA-encoded library screening. ACS Chem. Biol. 16, 2752–2756 (2021).
Mendes, K. R. et al. High-throughput identification of DNA-encoded IgG ligands that distinguish active and latent Mycobacterium tuberculosis infections. ACS Chem. Biol. 12, 234–243 (2017).
Doran, T. M. & Kodadek, T. A liquid array platform for the multiplexed analysis of synthetic molecule-protein interactions. ACS Chem. Biol. 9, 339–346 (2014).
Huang, Y., Deng, Y., Zhang, J., Meng, L. & Li, X. Direct ligand screening against membrane proteins on live cells enabled by DNA-programmed affinity labelling. Chem. Commun. 57, 3769–3772 (2021).
Huang, Y. et al. Selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. Nat. Chem. 13, 77–88 (2021).
Plais, L. & Scheuermann, J. Macrocyclic DNA-encoded chemical libraries: a historical perspective. RSC Chem. Biol. 3, 7–17 (2022).
Ge, R. et al. Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection. SLAS Discov. 27, 79–85 (2022).
Li, L. et al. Triazine-based covalent DNA-encoded libraries for discovery of covalent inhibitors of target proteins. ACS Med. Chem. Lett. 13, 1574–1581 (2022).
Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755–763 (2015).
Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015).
Zhong, Y. et al. Emerging targeted protein degradation tools for innovative drug discovery: from classical PROTACs to the novel and beyond. Eur. J. Med. Chem. 231, 114142 (2022).
Békés, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022).
Modell, A. E., Lai, S., Nguyen, T. M. & Choudhary, A. Bifunctional modalities for repurposing protein function. Cell Chem. Biol. 28, 1081–1089 (2021).
Belcher, B. P., Ward, C. C. & Nomura, D. K. Ligandability of E3 ligases for targeted protein degradation applications. Biochemistry 62, 588–600 (2023).
Faust, T. B., Donovan, K. A., Yue, H., Chamberlain, P. P. & Fischer, E. S. Small-molecule approaches to targeted protein degradation. Annu. Rev. Cancer Biol. 5, 181–201 (2020).
Gerry, C. J. & Schreiber, S. L. Unifying principles of bifunctional, proximity-inducing small molecules. Nat. Chem. Biol. 16, 369–378 (2020).
Winter, G. E. et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).
Lai, A. C. et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed. 55, 807–810 (2016).
Cowan, A. D. & Ciulli, A. Driving E3 ligase substrate specificity for targeted protein degradation: lessons from nature and the laboratory. Annu. Rev. Biochem. 91, 295–319 (2022).
Kramer, L. T. & Zhang, X. Expanding the landscape of E3 ligases for targeted protein degradation. Curr. Res. Chem. Biol. 2, 100020 (2022).
Chana, C. K. et al. Discovery and structural characterization of small molecule binders of the human CTLH E3 ligase subunit GID4. J. Med. Chem. 65, 12725–12746 (2022).
Mason, J. W. et al. DNA-encoded library (DEL)-enabled discovery of proximity-inducing small molecules. Preprint at bioRxiv https://doi.org/10.1101/2022.10.13.512184 (2022).
Chen, Q. et al. Optimization of PROTAC ternary complex using DNA encoded library approach. ACS Chem. Biol. 18, 25–33 (2023).
Shin, M. H., Lee, K. J. & Lim, H. S. DNA-encoded combinatorial library of macrocyclic peptoids. Bioconjug. Chem. 30, 2931–2938 (2019).
Lee, K. J., Bang, G., Kim, Y. W., Shin, M. H. & Lim, H. S. Design and synthesis of a DNA-encoded combinatorial library of bicyclic peptoids. Bioorg. Med. Chem. 48, 116423 (2021).
Cochrane, W. G. et al. Activity-based DNA-encoded library screening. ACS Comb. Sci. 21, 425–435 (2019).
MacConnell, A. B., Price, A. K. & Paegel, B. M. An integrated microfluidic processor for DNA-encoded combinatorial library functional screening. ACS Comb. Sci. 19, 181–192 (2017).
Benhamou, R. I. et al. DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor. Proc. Natl Acad. Sci. USA 119, e2114971119 (2022).
Chen, Q. et al. Expanding the DNA-encoded library toolbox: identifying small molecules targeting RNA. Nucleic Acids Res. 50, E67 (2022).
Chan, A. I., McGregor, L. M., Jain, T. & Liu, D. R. Discovery of a covalent kinase inhibitor from a DNA-encoded small-molecule library × protein library selection. J. Am. Chem. Soc. 139, 10192–10195 (2017).
Wang, D. Y. et al. Target identification of kinase inhibitor alisertib (MLN8237) by using DNA-programmed affinity labeling. Chemistry 23, 10906–10914 (2017).
Xie, J. et al. Selection of small molecules that bind to and activate the insulin receptor from a DNA-encoded library of natural products. iScience 23, 101197 (2020).
Li, J. et al. A DNA-encoded library for the identification of natural product binders that modulate poly (ADP-ribose) polymerase 1, a validated anti-cancer target. Biochem. Biophys. Res. Commun. 533, 241–248 (2020).
Wichert, M. et al. Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation. Nat. Chem. 7, 241–249 (2015).
Kulterer, O. C. et al. A microdosing study with 99mTc-PHC-102 for the SPECT/CT imaging of primary and metastatic lesions in renal cell carcinoma patients. J. Nucl. Med. 62, 360–365 (2021).
Petersen, L. K. et al. Screening of DNA-encoded small molecule libraries inside a living cell. J. Am. Chem. Soc. 143, 2751–2756 (2021).
Cai, B. et al. Selection of DNA-encoded libraries to protein targets within and on living cells. J. Am. Chem. Soc. 141, 17057–17061 (2019).
McCloskey, K. et al. Machine learning on DNA-encoded libraries: a new paradigm for hit finding. J. Med. Chem. 63, 8857–8866 (2020).
Xiong, F. et al. Discovery of TIGIT inhibitors based on DEL and machine learning. Front. Chem. 10, 982539 (2022).
Gartner, Z. J. et al. DNA-templated organic synthesis and selection of a library of macrocycles. Science 305, 1601–1605 (2004).
Halpin, D. R. & Harbury, P. B. DNA display I. Sequence-encoded routing of DNA populations. PLoS Biol. 2, 1015–1021 (2004).
Staz, A. L. et al. DNA-encoded chemical libraries. Nat. Rev. Methods Primers 2, 3 (2022).
MacConnell, A. B., McEnaney, P. J., Cavett, V. J. & Paegel, B. M. DNA-encoded solid-phase synthesis: encoding language design and complex oligomer library synthesis. ACS Comb. Sci. 17, 518–534 (2015).
Hackler, A. L., Fitzgerald, F. G., Dang, V. Q., Satz, A. L. & Paegel, B. M. Off-DNA DNA-encoded library affinity screening. ACS Comb. Sci. 22, 25–34 (2020).
Roy, A., Koesema, E. & Kodadek, T. High-throughput quality control assay for the solid-phase synthesis of DNA-encoded libraries of macrocycles. Angew. Chem. Int. Ed. 60, 11983–11990 (2021).
Mcgregor, L. M., Jain, T. & Liu, D. R. Identification of ligand − Target pairs from combined libraries of small molecules and unpurified protein targets in cell lysates. J. Am. Chem. Soc. 136, 3264–3270 (2014).
Blakskjaer, P., Heitner, T. & Hansen, N. J. V. Fidelity by design: yoctoReactor and binder trap enrichment for small-molecule DNA-encoded libraries and drug discovery. Curr. Opin. Chem. Biol. 26, 62–71 (2015).
Kochmann, S., Le, A. T. H., Hili, R. & Krylov, S. N. Predicting efficiency of NECEEM-based partitioning of protein binders from nonbinders in DNA-encoded libraries. Electrophoresis 39, 2991–2996 (2018).
Bao, J. et al. Predicting electrophoretic mobility of protein–ligand complexes for ligands from DNA-encoded libraries of small molecules. Anal. Chem. 88, 5498–5506 (2016).
Zhao, P. et al. Selection of DNA-encoded small molecule libraries against unmodified and non-immobilized protein targets. Angew. Chem. Int. Ed. 53, 10056–10059 (2014).
Shi, B., Deng, Y., Zhao, P. & Li, X. Selecting a DNA-encoded chemical library against non-immobilized proteins using a ‘ligate-cross-link-purify’ strategy. Bioconjug. Chem. 28, 2293–2301 (2017).
Sannino, A. et al. Critical evaluation of photo-cross-linking parameters for the implementation of efficient DNA-encoded chemical library selections. ACS Comb. Sci. 22, 204–212 (2020).
Denton, K. E. & Krusemark, C. J. Crosslinking of DNA-linked ligands to target proteins for enrichment from DNA-encoded libraries. MedChemComm 7, 2020–2027 (2016).
Ma, H. et al. PAC-FragmentDEL - photoactivated covalent capture of DNA-encoded fragments for hit discovery. RSC Med. Chem. 13, 1341–1349 (2022).
Zhou, Y. et al. DNA-encoded dynamic chemical library and its applications in ligand discovery. J. Am. Chem. Soc. 140, 15859–15867 (2018).
Reddavide, F. V., Lin, W., Lehnert, S. & Zhang, Y. DNA-encoded dynamic combinatorial chemical libraries. Angew. Chem. Int. Ed. 54, 7924–7928 (2015).
Deng, Y. et al. Selection of DNA-encoded dynamic chemical libraries for direct inhibitor discovery. Angew. Chem. Int. Ed. 59, 14965–14972 (2020).
Oehler, S. et al. Affinity selections of DNA-encoded chemical libraries on carbonic anhydrase IX-expressing tumor cells reveal a dependence on ligand valence. Chemistry 27, 8985–8993 (2021).
Acknowledgements
The authors thank A. Vieira for her valuable assistance and input. They thank M. O’Reilly for contributing DNA-encoded library architecture and selection figures. This work was supported by NIH R35 GM118062 and the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
A.A.P. and D.R.L. are co-inventors on patent applications on DNA-encoded libraries and their applications. D.R.L. is a consultant and co-founder of Exo Therapeutics, a company that uses DNA-encoded libraries.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
ClincalTrials.gov: https://clinicaltrials.gov/ct2/home
Protein Data Bank: https://www.rcsb.org/
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Peterson, A.A., Liu, D.R. Small-molecule discovery through DNA-encoded libraries. Nat Rev Drug Discov 22, 699–722 (2023). https://doi.org/10.1038/s41573-023-00713-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-023-00713-6
This article is cited by
-
Protein tyrosine phosphatase 1B in metabolic diseases and drug development
Nature Reviews Endocrinology (2024)
-
The glue degraders
Nature Biotechnology (2024)
-
A protein-templated selection approach for the identification of full ligands from DNA-encoded libraries
Nature Chemistry (2024)
-
Protein-templated ligand discovery via the selection of DNA-encoded dynamic libraries
Nature Chemistry (2024)
