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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).

The recent Cell publication by Xavier et al. (2026) demonstrates a groundbreaking “binder-first” strategy to target the immune scaffold protein CARD9 – a historically “undruggable” protein due to its coiled-coil (CC) domain architecture. This work highlights how DNA-encoded library (DEL) technology, provided by HitGen, played an important role in identifying a ligandable site and enabling the discovery of functional inhibitors with therapeutic potential for Crohn’s disease and inflammatory bowel disease (IBD).

A groundbreaking study from Duke University, led by Nobel Laureate Professor Robert J. Lefkowitz and Professor Howard A. Rockman, has identified a novel allosteric modulator of the β1-adrenergic receptor (β1AR) with a unique "PAM-antagonist" mechanism. The research, published in The Journal of Clinical Investigation, utilized HitGen OpenDEL™ and demonstrated significant potential for treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a life-threatening cardiac arrhythmia (Fig.1).

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by fibrotic tissue replacing normal lung parenchyma, leading to declined pulmonary function and dyspnea.

Macrocycles1 are generally defined as organic compounds with a ring of at least 12 atoms and hold in a chemical space between small molecules and biologics (Figure 1). With the constrained but somewhat flexible conformation, macrocycles often show higher affinity and selectivity to targets compared with their linear analogues. Therefore, macrocycles constitute an excellent tool for the targets which are difficult to modulate by traditional small molecules. With the enormous structural diversity, many of macrocycles display a wide range of functional capability and remarkable biological activities, which makes them as an important modality in drug discovery. More than 60 macrocycles have been approved as drugs by the U.S. Food and Drug Administration. Most of the macrocyclic drugs are natural products or their derivatives. Infectious disease, oncology, autoimmune disorders, and immunosuppressants are the major therapeutic indications of macrocyclic drugs.

The advancement of DNA Encoded Library (DEL) technology has been significant in recent decades. Beyond its conventional role in small molecule drug discovery, its integration into emerging fields has begun to garner increased interest. This can be attributed to its large chemical space, abundant Structure-Signal Relationship (SSR) data, and inherent DNA conjugation properties. In this context, we will explore alternative applications of DEL technology. It is postulated that with the continuous expansion of the DEL field and technological progression, more applications are yet to be unveiled.

As one of the largest and most functionally diverse gene families, kinases have been recognized as key regulators/mediators of biological signaling networks. More than 30% of drug development efforts target these enzymes in the past two decades. As of January 2024, more than 90 small molecule kinase drugs have been approved by the US Food and Drug Administration (FDA), with approximately 200 orally available protein kinase inhibitors in clinical trials. These compounds have had a significant impact on the treatment of both oncological and non-oncological conditions.

Although many covalent drugs were serendipitously discovered historically, covalent inhibitors were in general discouraged due to the concerns over their interference with biological assays and potential lack of selectivity. Over the past decades, rational design of covalent inhibitors has gained traction and garnered increased interest, particularly due to their stronger potency, prolonged target engagement, increased selectivity, and effectiveness to some drug-resistance mutants to reversible inhibitors.

DNA-encoded library (DEL) technology represents a revolutionary method in drug discovery. Unlike conventional approaches, DEL enables unparalleled exploration of chemical space, leading to the rapid identification of novel potent compounds.