DAC: A Game-Changer for Undruggable Targets
In the evolving landscape of targeted therapies, Degrader-Antibody Conjugates (DACs) are quickly emerging as a compelling new modality—combining the precise targeting capability of antibodies with the catalytic power of degraders. DACs are composed of 3 key components: a monoclonal antibody (mAb), payload, and chemical linker. This is similar to ADCs, although the cytotoxic payload of ADCs is replaced by a small molecule protein degrader, either a PROTAC or molecular glue. DACs are highly selective as they are designed to target a specific antigen expressed on the surface of a target cell. Upon internalization, lysosomal degradation, and release of the protein degrader into the target cell, the depletion of the disease-causing protein is enabled via the ubiquitin-proteasome system (Fig. 1).
Fig. 1 Degrader-Antibody Conjugates, digital image, from ( https://www.cullgen.com/dacs )
Compared to traditional degraders, DACs offer greater selectivity by delivering degraders directly to the target cell. Popular ADC payloads, such as DNA damaging agents and tubulin inhibitors, are very potent but can affect normal, non-diseased cells, posing the risk of off-target toxicity. In contrast, by using a degrader payload, DACs can act specifically on proteins of interest, increasing the overall therapeutic index and achieving comparable efficacy at lower doses—an advantage over both TPDs and ADCs.
Notably, DACs offer a promising alternative for “undruggable” targets such as GSPT1—one of the most common DAC targets, which lacks small-molecule binding pockets and remains challenging for traditional drug modalities. By combining the catalytic activity of TPDs with antibody-based delivery, DACs can overcome limitations of current approaches.
According to Beacon data, there are currently 47 DAC assets worldwide, 87% of which were added in 2024 and 2025. This growth in a short time frame supports the increased interest in DACs compared to other TPD modalities.
Fig. 2 Top Deals Overview
· As shown in Fig. 2, DACs are gaining investment traction across the industry. The DAC space is rapidly heating up, attracting both established pharma players and dedicated startups. Leading companies like Merck and BMS are expanding their DAC pipelines, while biotech innovators such as Firefly Bio and Bioloomics have secured millions in funding. DAC deals are gaining scale and strategic value.
Oncology is currently the main focus of DAC development. By providing tumor-specific selectivity and targeting previously "undruggable" proteins, DACs could provide safer, more effective solutions for hard-to-treat cancers such as solid tumors. The coming years could see DAC development expand into more non-oncology indications, such as autoimmune disease. As this novel modality continues to evolve, DACs are poised to unlock previously inaccessible biology and redefine targeted protein degradation.
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