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.

Konstantin Egon Seifert,Julissa Reimann,Martin Rust,Martin Bögemann,Andres Jan Schrader,Michael Schäfers,Christof Bernemann,Philipp Backhaus

Seminars in Nuclear Medicine

DOI: 10.1053/j.semnuclmed.2026.03.004

Abstract

Prostate-specific membrane antigen (PSMA)-targeted theranostics have transformed the diagnostic and therapeutic landscape of prostate cancer; however, clinically relevant limitations persist, including heterogeneous or absent PSMA expression in a substantial subset of tumors and dose-limiting off-target uptake in salivary glands, lacrimal glands and kidneys. Prostatic acid phosphatase (ACP3), expressed in more than 95% of prostate cancers, has re-emerged as a promising complementary and potentially alternative theranostic target. ACP3 demonstrates favorable biological characteristics, including high and consistent tumor expression, persistence in castration-resistant disease, and minimal expression in critical but non-cancerous tissues. Recent advances in ligand discovery using DNA-encoded chemical libraries have enabled the development of high-affinity ACP3-targeting compounds, with successful first-in-human molecular imaging with [68Ga]Ga-OncoACP3-DOTA PET. Early clinical data demonstrate competitive diagnostic performance compared with PSMA-PET, markedly reduced salivary/lacrimal gland and renal uptake, and advantageous pharmacokinetics characterized by increasing tumor uptake and improving tumor-to-background ratios over time. Preclinical and translational evidence further supports the feasibility of ACP3-targeted radioligand therapy. This review summarizes the biological features of ACP3, its historical and current role as a biomarker, and emerging therapeutic applications, with a primary focus on ACP3-targeted molecular imaging and radioligand therapy. The available evidence positions ACP3 as a compelling next-generation theranostic target with the potential to overcome key limitations of PSMA-based approaches and expand precision treatment options for patients with prostate cancer.

Xudong Wang , Zijian Liu , Xuanjing Shen , Yueyue Xia, Sixiu Liu, Nidhal Selmi, Yinan Song, Xiaojie Lu

ChemRxiv

DOI: 10.26434/chemrxiv.15001270/v1

Abstract

DNA-encoded library (DEL) technology has become an essential approach for accelerating hit discovery in drug development, yet its success is closely tied to the availability of robust and DNA-compatible reactions. Here we report a diboron-mediated strategy that leverages in situ generated Cu(I) to enable the efficient on-DNA construction of dihydroquinazolinones, a privileged heterocyclic scaffold with broad pharmacological relevance. This transformation proceeds via selective nitro group reduction followed by intramolecular cyclization with aldehydes or ketones under mild, aqueous-compatible conditions. The method tolerates diverse building blocks, delivering high conversions across a panel of substrates. By providing a reliable and atom-economical route to dihydroquinazolinones directly on DNA, this study expands the accessible chemical space of DELs and enriches the toolbox of DNA-compatible heterocycle syntheses.

A recent review published in Bioconjugate Chemistry by Marinier et al. (2026) shows that DNA-encoded libraries (DELs), long established for therapeutic small-molecule discovery, represent an underutilized yet highly promising platform for the rapid, parallel development of next-generation molecular probes – particularly for live-cell imaging, targeted radioimaging, and personalized theranostics. DEL-derived targeting moieties can be efficiently and modularly converted into high-affinity, high-selectivity optical or radiolabeled probes – including dual-use agents that simultaneously enable precise diagnosis and effective therapy (Figure 1).A recent review published in Bioconjugate Chemistry by Marinier et al. (2026) shows that DNA-encoded libraries (DELs), long established for therapeutic small-molecule discovery, represent an underutilized yet highly promising platform for the rapid, parallel development of next-generation molecular probes – particularly for live-cell imaging, targeted radioimaging, and personalized theranostics. DEL-derived targeting moieties can be efficiently and modularly converted into high-affinity, high-selectivity optical or radiolabeled probes – including dual-use agents that simultaneously enable precise diagnosis and effective therapy (Figure 1).

Figure 1. DEL for new molecular probe discovery

1. Trends in molecular probe development

Conventional probes include several different types of structures. Non-targeted fluorescent dyes were developed and used in early years, but that resulted in high background and poor selectivity. Metabolic radiotracers like [¹⁸F]FDG lack target specificity. Bi-functional tracers with large targeting moiety (larger peptides, aptamers and antibodies) suffer from limited tissue penetration, instability, and complex manufacturing. Small molecules targeting moiety offer compelling advantages – as targeting ligands, they provide excellent cell permeability, metabolic stability, oral bioavailability potential, shelf life, and scalable synthesis – making them ideal scaffolds for bi-functional probes. An effective approach to discover suitable small molecules for probe development is in urgent need.

2. Development of DEL technology and its role in new probe discovery

DEL technology has undergone rapid development over the past few decades. Various DEL construction strategies (e.g., dsDEL, ssDEL, Dynamic DEL, OBOC-DEL), DNA-compatible chemistries (amide coupling, Suzuki cross-coupling, reductive amination), screening modalities (target-immobilized pulldown, live-cell selection, target-agnostic cell-based assays), and hit validation workflows (on-DNA/off-DNA resynthesis, FP, SPR, ELISA) have been reported. These advances enabled ultra-high-throughput screening of billions of compounds against diverse, challenging targets – including membrane proteins, intracellular targets, whole cells, pathogens, mRNA, and even patient-derived samples. The DNA tag acts as a robust, solvent-exposed conjugation handle – enabling rational, modular reporter attachment without compromising binding affinity. Highly selective molecules arise from DEL’s vast chemical diversity and compatibility with counter-screening (e.g., antitarget cells), while rapid screening (<1 week) makes fast probe development possible.

3. DEL-derived molecular probe development cases

The following figure shows some examples of DEL hit-based probe discovery (Figure 2). Some of them exhibit promising prospects:

• CAIX (Carbonic Anhydrase IX)-targeting optical probe: 3b (Kd = 7 nM) enabled ex vivo tumor imaging and successfully guided CAIX-expressing SK-RC-52 tumor lysis in the presence of fluorescein-specific UniCAR T-cells;
• PSMA (Prostate-Specific Membrane Antigen)-targeting probes: 7b/8b showed nanomolar affinity, high selectivity over antitarget GCP3 (glutamate carboxypeptidase III), and selective cellular internalization; 7c demonstrated reduced kidney uptake compared with Pluvicto® treatment to mitigate nephrotoxicity;
• CAIX-targeting radioactive probes: [¹⁷⁷Lu]-labeled 6d achieved near-exclusive tumor accumulation in xenografts; [⁶⁸Ga]-labeled 6e is currently in Phase I clinical trial for renal cancer.

Figure 2. Left: Structures of validated DEL hits against known cancer-associated antigens (R = DNA exit vector). Right: Structure of the optimized probes.

4. Future directions and summary

The successful cases shown above prove the potential of DEL-based new molecular probe development. Some challenges still need to be addressed, including cost and access barriers for DELs, as well as low retention and short circulation half-life. Commercial DEL products like HitGen OpenDEL™, as well as academic DEL platforms, will democratize the access to high-quality DELs. Predictive models can be built based on integration of AI/ML to extract structure-affinity relationships from DEL data. Broader adoption of covalent DEL binders (e.g., acrylamide warheads) will help enhance retention and theranostic efficacy. Incorporation of albumin-binding motifs is beneficial for extending circulation half-life. Ultimately, DEL is positioned as a foundational, data-rich, and highly adaptable technology uniquely suited to accelerate the development of personalized, next-generation molecular probes and theranostics.

Reference:

Julien Poupart, Sunit Kumar Jana, Sasmita Tripathy, and Anne Marinier. DNA-Encoded Libraries (DELs) for Discovering New Molecular Probes: Application to Live-Cell Bioimaging and Personalized Theranostics. Bioconjugate Chem. 2026, 37, 3, 511–525. https://pubs.acs.org/doi/10.1021/acs.bioconjchem.5c00661

Hao Guo, Zitao Li, Gaonan Wang, Biyu Zhang, Mengxue Wang, Lu Liu, Alexander L. Satz, Wenji Su, Letian Kuai, Qi Zhang

Bioconjugate Chemistry 

DOI: 10.1021/acs.bioconjchem.5c00655

Abstract

This study presents a DNA-compatible synthesis of diverse N-fused imidazopyridines via a catalyst-free Ugi-type multicomponent reaction using TMSCN as a functional isonitrile equivalent. The desilylation activation occurs efficiently in water without additional catalysts. The method exhibits a broad substrate scope for aldehydes and heterocyclic amidines and excellent chemoselectivity, underscoring its utility for constructing privileged heteroaromatic scaffolds in DNA-encoded library technology.

Louis Plyer, Alexey A. Orlov, Tagir N. Akhmetshin, Erik Yeghyan, Fanny Bonachera, Dragos Horvath, Alexandre Varnek

Molecular Informatics

DOI: 10.1002/minf.70026

Abstract

The growing number and size of DNA‐encoded libraries (DELs), together with the vast space of possible DEL designs, demand interpretable and scalable criteria for selecting which libraries to construct and screen against a given target. An ideal target‐focused DEL shows both strong similarity with an active reference compound collection and high intra‐DEL diversity. Chemography with Generative Topographic Mapping (GTM) was shown to be a promising approach for selecting DELs, offering both intuitive visualization and fast quantitative analysis scalable to thousands of DEL designs. This is achieved by defining each library by a “stand‐alone” vector, the comparison of which precludes costly pairwise inter‐molecular similarity calculations. However, the extent to which such “stand‐alone” (SA) approaches in general, and GTM‐derived SA metrics in particular, recover DELs that are reference‐proximal and chemically diverse as evaluated by conventional compound pair‐matching (CP) metrics in the initial descriptor space remains insufficiently characterized. In this article, the comparative analysis of the Morgan count fingerprint‐based chemical‐library similarity versus GTM‐derived metrics, using 100 diverse DEL subsets and a reference set of compounds tested against cyclin‐dependent kinase 2 (CDK2) from ChEMBL, was performed. GTM‐based SA metrics provide robust approximations for “gold standard” molecular descriptor space CP metrics for DEL selection: Spearman rank correlations fall in the 0.6–0.7 range. Our results demonstrate that GTM helps to identify DELs that best span the reference space according to same “gold standard” molecular descriptor space metrics: SA GTM‐driven rankings of libraries achieve enrichment factors at 5% (EF5%) of 4–12 (in terms of finding “gold standard” top libraries within the 5% best ranked by GTM)—always picking 2 out of the top 3 libraries. The accompanying two‐dimensional landscapes make intra‐ and interlibrary diversity visually accessible, supporting rapid, interpretable screening of alternative DEL designs. Collectively, these results position GTM as an efficient tool for chemical‐library similarity assessment and target‐focused DEL selection.