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A central hub to connect with global DEL professionals, access the latest industry insights and product updates, and collaborate to accelerate drug discovery.

DEL Hunter

  • DEL-Related Publications

    Recent Advances in GPCR Ligand Discovery Using DNA-Encoded Library Technology: From Affinity Binding to Functional Bias and Allosteric Modulation

    Ruolan Zhou, Jiajia Wang, Xiang Li, Yulong An ACS Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.6c00113 Abstract DNA-encoded library (DEL) technology has emerged as a transformative platform for the discovery of bioactive small molecules against challenging therapeutic targets including G protein-coupled receptors (GPCRs). As a clinically pivotal class of membrane-bound targets, GPCRs pose inherent challenges in the discovery of novel ligands. This Microperspective highlights recent methodological advances (2015–2026) that enable DEL selections against GPCRs, thereby facilitating the identification of diverse ligand modalities, including agonists, antagonists, allosteric modulators, and biased ligands. Furthermore, we discuss current challenges and future directions in the application of DEL technology to GPCR drug discovery, with a specific emphasis on opportunities in receptor stabilization, selection strategy design, and computational method development.

  • DEL-Related Publications

    DNA-Encoded Libraries for the Discovery of E3 Ligase Ligands

    Lulu Wen,Qingqing Zhang,Zhiqiang Duan,Rui Jin,Xiaojie Lu ChemMedChem DOI: 10.1002/cmdc.202501032 Abstract DNA-encoded library (DEL) technology has emerged as a powerful tool to accelerate drug discovery, and its application has expanded to challenging targets such as E3 ubiquitin ligases, whose ligands are essential for the development of targeted therapies, including proteolysis-targeting chimeras (PROTACs). In this review, we summarize recent advances in the use of DELs for the discovery of small-molecule non-covalent E3 ligase ligands and discuss their advantages in hit-to-lead optimization and the design of targeted protein degradation systems. Furthermore, we highlight the potential and application basis of covalent DELs and DNA-encoded cyclic peptide libraries, which together outline promising future directions for DEL-based discovery of E3 ligase ligands. Emerging DEL-based strategies for the direct discovery and optimization of TPD molecules are also discussed.

  • DEL-Related Publications

    Assessing the Generalizability of Machine Learning and Physics Methods for DNA-Encoded Libraries

    Marissa D Dolorfino, Daniel Santos Perez, Yao Fu, Shu-Hang Lin, Sean McCarty, Matthew James O'Meara, Terra Sztain bioRxiv - Biophysics DOI: 10.64898/2026.04.18.719394 Abstract DNA-encoded libraries (DELs) enable ultra-large screening of billions of molecules simultaneously. However, various limitations of DELs have prompted interest in training machine learning (ML) models on these large datasets to extrapolate predictions to non-DEL compounds. A recent NeurIPS competition revealed that even top performing ML models trained on DEL data failed at generalizing to out-of-distribution (OOD) chemical space. We investigated whether integrating structural modeling could bridge this generalization gap. We systematically assessed state-of-the-art ML, docking, and co-folding methods with three biologically diverse protein targets screened against libraries containing multiple DEL synthesis formats, and show that while ML excels in-distribution, the optimal approach for OOD hit discrimination performance is both target and ligand dependent. We conclude that, regardless of performance reported in aggregated benchmarks, rigorous, system-dependent pilot testing is critical for reliable virtual screening predictions. We provide these workflows and analysis tools in an open-source package: DEL-iver.

  • DEL-Related Publications

    Massive barcode-free chemical screenings enable the discovery of bioactive macrocycles with passive membrane permeability

    J. Miguel Mata, Jingming Liu, Sean M. McKenna, Edith van der Nol, Marije Havermans, Ruud Delwel, Mike Filius, Chirlmin Joo, Maura Vallaro, Giulia Caron, Sebastian J. Pomplun Nature Communications DOI: 10.1038/s41467-026-71641-3 Abstract Synthetic macrocycles offer exceptional potential as therapeutics. However, most high-throughput discovery platforms rely on genetically encoded libraries of large peptide macrocycles, which typically are not optimized for drug like properties. Fully synthetic libraries offer greater flexibility in accessing broader chemical space. Leveraging recent advances in mass spectrometry based library techniques, here we report CycloSEL (Cyclic Self-Encoded Libraries), an end-to-end workflow, that screens synthetic macrocycle libraries enriched in drug-like ‘beyond rule of five’ features. The workflow relies on affinity selections and hit identification by tandem mass spectrometry, eliminating the need for genetic barcodes. We construct a 16 million-member library and validate the approach against the oncology target carbonic anhydrase IX, achieving robust enrichment and accurate identification of true binders. Applying CycloSEL to the acute myeloid leukemia target WD repeat-containing protein 5 (WDR5) yields a macrocycle with subnamolar affinity, and potent inhibition of the WDR5–Mixed-Lineage Leukemia 1 (MLL1) interaction. Subsequent modifications produce a chameleonic macrocycle with passive membrane permeability, serum stability, and anti-proliferative activity in leukemia cells. Together, these results demonstrate that CycloSEL enables discovery of drug-like macrocycles from fully synthetic libraries for intracellular targets.

  • DEL Insights

    DEL Insight | Solid-phase DEL: Applications and Future Prospects

    As the field of traditional DNA-Encoded Library (DEL) chemistry reaches maturity, expectations for library quality have become increasingly exacting. Beyond conventional optimizations focused on purification protocols and reaction yields, a growing number of research groups have pioneered solid-phase synthesis strategies to enhance peptide library purity. Here, we present and discuss the key insights gleaned from three recent publications on solid-phase DEL derivatives. Shiyu Chen et al. pioneered a solid-phase purification strategy for DNA-encoded peptide libraries (PDELs) by engineering a modified Fmoc (mFmoc) protecting group equipped with a terminal azido1. This design enables the specific immobilization of desired peptide intermediates onto alkyne-functionalized controlled pore glass (CPG) beads via copper-free click chemistry following each coupling step (Fig. 1). After rigorous washing to eliminate unreacted building blocks and truncated byproducts, the pure products are released through standard Fmoc deprotection. This "capture-and-release" cycle successfully facilitated the construction of the longest reported five-round PDEL with purity exceeding 95%, effectively breaking the conventional four-round synthesis barrier. (Solid DEL-1) Fig. 1: Iterative cycles of generating a purified DNA-encoded peptide library with mFmoc-protected amino acids. The desired DNA-encoded peptide is isolated after immobilization and purification (Solid DEL-1). The group of Jörg Scheuermann developed another dual-linker solid-phase synthesis strategy on magnetic beads to achieve "self-purifying" release of DELs (Fig. 2)2. This solid-phase platform not only facilitates the synthesis of high-purity five-cycle desired peptide compounds but also significantly expands the compatible reaction scope to include water-free conditions, enabling transformations previously inaccessible in traditional aqueous DEL synthesis, such as the SnAP cyclization reaction and acid-mediated Boc-deprotection. However, this synthetic strategy is quite tedious. (Solid DEL-2) Fig. 2: Synthetic strategy used for "self-purifying" release of DEL (Solid DEL-2). Brian M. Paegel has pioneered an alternative solid-phase DNA-encoded library (DEL) synthesis strategy that integrates the "one-bead-one-compound" (OBOC) approach3. In this method, library members are constructed on solid-phase microbeads and linked to DNA tags via a photocleavable linker. This design facilitates the physical isolation and light-triggered release of desired peptide compounds, thereby enabling a broader spectrum of screening modalities, including activity-based assays and cellular phenotypic screening. However, this approach is inherently limited to a library size of 104–106 members, as it relies on the individual screening of compounds on discrete physical beads (Fig. 3). (Solid DEL-3) Fig. 3: Synthetic strategy used for one-bead-one-compound of DEL (Solid DEL-3). Collectively, these three solid-phase DEL design paradigms offer new insights into the future of peptide DEL library construction. They suggest that we can strategically leverage emerging technologies to fundamentally enhance peptide DEL library quality. Aligning with this evolving paradigm, HitGen is also exploring the introduction of novel solid-phase methodologies to elevate the quality of our peptide libraries. We anticipate that, in the near future, these innovations will be successfully translated into practice, pointing a new direction for the next generation of DEL synthesis.   Reference: 1. He Q, Wang Y, Tang X, et al. Enhanced screening via a pure DNA-encoded peptide library enabled by an Fmoc modification. Proc Natl Acad Sci U S A. 2026;123(8):e2524999123. doi:10.1073/pnas.2524999123 2. Keller M, Petrov D, Gloger A, et al. Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis. Science. 2024;384(6701):1259-1265. doi:10.1126/science.adn3412 3. Dixit A, Paegel BM. Solid-phase DNA-encoded library synthesis: a master builder's instructions. Nat Protoc. 2026;21(2):542-581. doi:10.1038/s41596-025-01190-4

  • DEL-Related Publications

    Tandem In Situ Nitro Reduction and Cyclization for the On-DNA Synthesis of Traditionally Privileged Skeletons

    Xuanjing Shen, Xudong Wang, Zijian Liu, Yueyue Xia, Xinyuan Wu, Hanqing Zhao, Caini He, Hongbin Xu, Zhiqiang Duan Bioconjugate Chemistry DOI: 10.1021/acs.bioconjchem.6c00057 Abstract The development of DNA-encoded library (DEL) technology is contingent upon robust and DNA-compatible reactions to expand accessible chemical space. Tandem transformations, which combine functional group interconversion and scaffold construction in one step, are particularly attractive for streamlining on-DNA synthesis. Herein, we report a copper-mediated tandem reaction conducted under mild, aqueous conditions that enables the in situ reduction of nitro groups followed by reductive amination with aldehydes. This DNA-compatible protocol efficiently furnishes secondary amines directly from nitro substrates, circumventing the need for prereduction. Moreover, the methodology can be extended to o-nitroaniline derivatives, providing efficient one-pot access to benzimidazole scaffolds through tandem nitro reduction and cyclization with aldehydes. Compared to conventional stepwise sequences requiring isolated intermediates, this strategy provides a more streamlined and atom-economical route for constructing privileged pharmacophores directly on DNA.

Product & Services

OpenDEL™ - Small Molecule

Starting Your Journey to Access the Vast Chemical Space

The Kit

  • 57 Libraries
  • ~3.8Bn compounds
  • 10 DEL samples

 

To Access

  • Fully Enumerated Molecules
  • Building Block Structures
  • DNA Codon Sequences
  • Scaffolds Information

 

✔ No Structure Disclosure Fee

✔ No Compound IP License Fee
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OpenDEL™ - Small Molecule
01

OpenDEL™ Screening

OpenDEL™ screening is carried out by our team of experienced professionals, proficient in handling over 50 different target types including protein-protein interactions, kinases, enzymes, transcription factors, and RNA targets. Our team typically completes the screening experiments within 1-2 weeks. 
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OpenDEL™ Screening
02

OpenDEL™ Sequencing

HitGen offers high-quality and gold sequencing service includes. 
  • Global Sample Shipment

  • Outstanding Sequencing Quality

  • Lightning-speed Result Delivery

  • Diverse Sequencing Options

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OpenDEL™ Sequencing
03

OpenDEL™ Hit Proposal

Analyzing DEL selection data and choosing the right compounds for follow-up necessitates multidisciplinary expertise encompassing biology, computational science, and chemistry. This includes a deep understanding of the experimental design and mechanisms of action (MOAs) in biology, data processing and analysis in computational science, and aspects of both synthetic and DEL chemistry
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OpenDEL™ Hit Proposal
04

OpenDEL™ Off-DNA Synthesis

HitGen Chemical Services: Innovation-Driven and Precision-Empowered.

We transform your DEL hits into tangible results by delivering the pure, complex structures critical for validating discoveries and accelerating their advancement.

Choose Your Path:

A. Traditional Chemical Synthesis @ HitGen 
B. High Throughput Chemical Synthesis @ HitGen

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OpenDEL™ Off-DNA Synthesis
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What are people in the community saying?

Connect with peers. Access breakthrough science. Spark your next discovery.

  • HitGen
    HitGen

    Marissa D Dolorfino, Daniel Santos Perez, Yao Fu, Shu-Hang Lin, Sean McCarty, Matthew James O'Meara, Terra Sztain

    bioRxiv - Biophysics

    DOI: 10.64898/2026.04.18.719394

    Abstract

    DNA-encoded libraries (DELs) enable ultra-large screening of billions of molecules simultaneously. However, various limitations of DELs have prompted interest in training machine learning (ML) models on these large datasets to extrapolate predictions to non-DEL compounds. A recent NeurIPS competition revealed that even top performing ML models trained on DEL data failed at generalizing to out-of-distribution (OOD) chemical space. We investigated whether integrating structural modeling could bridge this generalization gap. We systematically assessed state-of-the-art ML, docking, and co-folding methods with three biologically diverse protein targets screened against libraries containing multiple DEL synthesis formats, and show that while ML excels in-distribution, the optimal approach for OOD hit discrimination performance is both target and ligand dependent. We conclude that, regardless of performance reported in aggregated benchmarks, rigorous, system-dependent pilot testing is critical for reliable virtual screening predictions. We provide these workflows and analysis tools in an open-source package: DEL-iver.

  • HitGen
    HitGen

    Lulu Wen,Qingqing Zhang,Zhiqiang Duan,Rui Jin,Xiaojie Lu

    ChemMedChem

    DOI: 10.1002/cmdc.202501032

    Abstract

    DNA-encoded library (DEL) technology has emerged as a powerful tool to accelerate drug discovery, and its application has expanded to challenging targets such as E3 ubiquitin ligases, whose ligands are essential for the development of targeted therapies, including proteolysis-targeting chimeras (PROTACs). In this review, we summarize recent advances in the use of DELs for the discovery of small-molecule non-covalent E3 ligase ligands and discuss their advantages in hit-to-lead optimization and the design of targeted protein degradation systems. Furthermore, we highlight the potential and application basis of covalent DELs and DNA-encoded cyclic peptide libraries, which together outline promising future directions for DEL-based discovery of E3 ligase ligands. Emerging DEL-based strategies for the direct discovery and optimization of TPD molecules are also discussed.

  • HitGen
    HitGen

    Ruolan Zhou, Jiajia Wang, Xiang Li, Yulong An

    ACS Medicinal Chemistry Letters

    DOI: 10.1021/acsmedchemlett.6c00113

    Abstract

    DNA-encoded library (DEL) technology has emerged as a transformative platform for the discovery of bioactive small molecules against challenging therapeutic targets including G protein-coupled receptors (GPCRs). As a clinically pivotal class of membrane-bound targets, GPCRs pose inherent challenges in the discovery of novel ligands. This Microperspective highlights recent methodological advances (2015–2026) that enable DEL selections against GPCRs, thereby facilitating the identification of diverse ligand modalities, including agonists, antagonists, allosteric modulators, and biased ligands. Furthermore, we discuss current challenges and future directions in the application of DEL technology to GPCR drug discovery, with a specific emphasis on opportunities in receptor stabilization, selection strategy design, and computational method development.

  • HitGen
    HitGen

    J. Miguel Mata, Jingming Liu, Sean M. McKenna, Edith van der Nol, Marije Havermans, Ruud Delwel, Mike Filius, Chirlmin Joo, Maura Vallaro, Giulia Caron, Sebastian J. Pomplun

    Nature Communications

    DOI: 10.1038/s41467-026-71641-3

    Abstract

    Synthetic macrocycles offer exceptional potential as therapeutics. However, most high-throughput discovery platforms rely on genetically encoded libraries of large peptide macrocycles, which typically are not optimized for drug like properties. Fully synthetic libraries offer greater flexibility in accessing broader chemical space. Leveraging recent advances in mass spectrometry based library techniques, here we report CycloSEL (Cyclic Self-Encoded Libraries), an end-to-end workflow, that screens synthetic macrocycle libraries enriched in drug-like ‘beyond rule of five’ features. The workflow relies on affinity selections and hit identification by tandem mass spectrometry, eliminating the need for genetic barcodes. We construct a 16 million-member library and validate the approach against the oncology target carbonic anhydrase IX, achieving robust enrichment and accurate identification of true binders. Applying CycloSEL to the acute myeloid leukemia target WD repeat-containing protein 5 (WDR5) yields a macrocycle with subnamolar affinity, and potent inhibition of the WDR5–Mixed-Lineage Leukemia 1 (MLL1) interaction. Subsequent modifications produce a chameleonic macrocycle with passive membrane permeability, serum stability, and anti-proliferative activity in leukemia cells. Together, these results demonstrate that CycloSEL enables discovery of drug-like macrocycles from fully synthetic libraries for intracellular targets.

  • HitGen
    HitGen

    As the field of traditional DNA-Encoded Library (DEL) chemistry reaches maturity, expectations for library quality have become increasingly exacting. Beyond conventional optimizations focused on purification protocols and reaction yields, a growing number of research groups have pioneered solid-phase synthesis strategies to enhance peptide library purity. Here, we present and discuss the key insights gleaned from three recent publications on solid-phase DEL derivatives.

    Shiyu Chen et al. pioneered a solid-phase purification strategy for DNA-encoded peptide libraries (PDELs) by engineering a modified Fmoc (mFmoc) protecting group equipped with a terminal azido1. This design enables the specific immobilization of desired peptide intermediates onto alkyne-functionalized controlled pore glass (CPG) beads via copper-free click chemistry following each coupling step (Fig. 1). After rigorous washing to eliminate unreacted building blocks and truncated byproducts, the pure products are released through standard Fmoc deprotection. This "capture-and-release" cycle successfully facilitated the construction of the longest reported five-round PDEL with purity exceeding 95%, effectively breaking the conventional four-round synthesis barrier. (Solid DEL-1)

    Fig. 1: Iterative cycles of generating a purified DNA-encoded peptide library with mFmoc-protected amino acids. The desired DNA-encoded peptide is isolated after immobilization and purification (Solid DEL-1).

    The group of Jörg Scheuermann developed another dual-linker solid-phase synthesis strategy on magnetic beads to achieve "self-purifying" release of DELs (Fig. 2)2. This solid-phase platform not only facilitates the synthesis of high-purity five-cycle desired peptide compounds but also significantly expands the compatible reaction scope to include water-free conditions, enabling transformations previously inaccessible in traditional aqueous DEL synthesis, such as the SnAP cyclization reaction and acid-mediated Boc-deprotection. However, this synthetic strategy is quite tedious. (Solid DEL-2)

    Fig. 2: Synthetic strategy used for "self-purifying" release of DEL (Solid DEL-2).

    Brian M. Paegel has pioneered an alternative solid-phase DNA-encoded library (DEL) synthesis strategy that integrates the "one-bead-one-compound" (OBOC) approach3. In this method, library members are constructed on solid-phase microbeads and linked to DNA tags via a photocleavable linker. This design facilitates the physical isolation and light-triggered release of desired peptide compounds, thereby enabling a broader spectrum of screening modalities, including activity-based assays and cellular phenotypic screening. However, this approach is inherently limited to a library size of 104–106 members, as it relies on the individual screening of compounds on discrete physical beads (Fig. 3). (Solid DEL-3)

    Fig. 3: Synthetic strategy used for one-bead-one-compound of DEL (Solid DEL-3).

    Collectively, these three solid-phase DEL design paradigms offer new insights into the future of peptide DEL library construction. They suggest that we can strategically leverage emerging technologies to fundamentally enhance peptide DEL library quality. Aligning with this evolving paradigm, HitGen is also exploring the introduction of novel solid-phase methodologies to elevate the quality of our peptide libraries. We anticipate that, in the near future, these innovations will be successfully translated into practice, pointing a new direction for the next generation of DEL synthesis.

     

    Reference:

    1. He Q, Wang Y, Tang X, et al. Enhanced screening via a pure DNA-encoded peptide library enabled by an Fmoc modification. Proc Natl Acad Sci U S A. 2026;123(8):e2524999123. doi:10.1073/pnas.2524999123

    2. Keller M, Petrov D, Gloger A, et al. Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis. Science. 2024;384(6701):1259-1265. doi:10.1126/science.adn3412

    3. Dixit A, Paegel BM. Solid-phase DNA-encoded library synthesis: a master builder's instructions. Nat Protoc. 2026;21(2):542-581. doi:10.1038/s41596-025-01190-4

  • HitGen
    HitGen

    Maria Staikopoulou, Haitham Hassan

    Drug Discovery Today

    DOI: 10.1016/j.drudis.2026.104658

    Highlight

    • A comprehensive review of kinase inhibitors discovered via DNA-encoded libraries (DELs) from 2009 to 2025.
    • Analysis of chemical diversity, binding interactions and optimisation strategies driving DEL-based kinase inhibitor discovery.
    • Mapping of 22 kinase targets across 17 families, including CMGC, tyrosine kinase, TKL and STE superfamilies.
    • Strategic design recommendations for DEL scaffolds, heterocycles and covalent warheads to enhance selectivity and druglike properties.
    • Future directions integrating DELs with artificial intelligence/machine learning and hybrid screening approaches to accelerate the development of selective kinase inhibitors.

    Abstract

    In this review, we summarise and analyse the structures and key characteristics of kinase inhibitors identified through DNA-encoded libraries (DELs) from 2009 to 2025. We focus on their chemical diversity, binding interactions and optimisation strategies that have driven progress in DEL-based kinase inhibitor discovery. Representative case studies highlight innovative approaches and successes in addressing therapeutic challenges associated with kinases. We also examine the general physicochemical properties of the identified compounds and map the kinase families most frequently targeted by DELs. Overall, 47 initial hits and 17 leads were evaluated for 24 kinase targets across 19 families. Our aim is to inspire further advancements in DEL technology and promote its application in the selective and efficient discovery of kinase inhibitors to accelerate drug development.

    1-s2.0-S1359644626000632-ga1_lrg.jpg

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