The new review, authored by Shun-Ran Li, Meng-Qian Yu, and colleagues at Hangzhou Normal University and collaborating institutions, systematically surveys the explosion of dual- and multi-target degraders reported between 2023 and 2026. Its central premise is that complex diseases rarely depend on a single molecular culprit. Cancer and neurodegenerative disorders are governed by redundant and compensatory signaling networks, so when one driver protein is eliminated, others rush to fill the gap. Conventional single-target PROTACs, however powerful, can be undermined by this biological backup system. Dual PROTACs attempt to solve the problem in a single chemical entity, collapsing what would otherwise be a combination of two drugs into one compound with one set of pharmacokinetics.

The authors organize the growing catalog of dual degraders into two broad design classes. The first targets homologous proteins within the same family, where structural similarity can be exploited by a single warhead that binds both. Cyclin-dependent kinases have been a particular focus, with dual degraders reported for CDK4/6, CDK2/5, and CDK12/13, the latter exemplified by the orally bioavailable triple-negative breast cancer candidate DN1679. The BCL-2 family of apoptosis regulators has yielded dual BCL-2/BCL-xL degraders with improved anti-leukemic activity, and the field has now seen first-in-class degraders for the bromodomain proteins BAZ2A and BAZ2B as well as dual histone deacetylase degraders, including HDAC3/HDAC8 molecules that revealed new roles for histone acetylation in gene regulation.

The second, and pharmacologically more ambitious, class targets two distinct proteins sitting on different but interconnected disease pathways. Here the review catalogues an impressive roster: ERα/aromatase degraders designed to overcome endocrine-resistant breast cancer by hitting both the receptor and the enzyme that produces its activating estrogen; α-synuclein/tau degraders aimed at the protein aggregates that define Parkinson’s and Alzheimer’s disease; BET/HDAC and CBP/BRD4 degraders that combine epigenetic readers and erasers in one molecule; PI3K/mTOR degraders that suppress the entire eponymous survival pathway; and FLT3/CHK1 degraders that pair an oncogenic kinase with a checkpoint kinase to attack acute myeloid leukemia from two directions.

The technical heart of the review lies in its dissection of structure-activity relationships. Linker chemistry is where dual PROTACs live or die. Because a single molecule must accommodate two target-binding events, the linker length, attachment point, and flexibility determine not only potency but the ternary geometry between target, PROTAC, and E3 ligase that licenses ubiquitin transfer. Several case studies illustrate the point. Dual BCL-xL/BCL-w degraders were built by exploiting the bis(sulfonyl)benzene ring of the clinical inhibitor ABT-263 as a linkage vector, showing how careful warhead decoration can convert a blocker into a degrader. In the FLT3/CHK1 program, systematic linker scans revealed how marginal changes in length flipped degradation selectivity between the two kinases. The authors emphasize that hook effects, hook-like concentration dependence in which excess PROTAC saturates both binding sites separately and aborts the ternary complex, remain a persistent design trap requiring careful dose-response characterization.

E3 ligase selection emerges as another decisive variable. Most reported dual degraders recruit either the von Hippel-Lindau (VHL) ligase or cereblon (CRBN), reflecting the maturity of their ligand chemistries. CRBN-recruiting degraders derived from pomalidomide and related immunomodulatory drugs have proven especially productive for kinases and transcriptional regulators, while VHL ligands dominate among cytosolic and nuclear targets. But the review is blunt about the field’s narrow toolkit: the reliance on just two or three E3 ligases limits tissue selectivity, constrains the design space for dual targets, and contributes to off-target degradation of neo-substrates such as IKZF1 and IKZF3. Expanding the E3 ligase repertoire, including tumor-selective or tissue-specific ligases, is flagged as a priority for next-generation design.

Among the milestones the review highlights are the first dual degraders aimed at non-kinase epigenetic regulators and, strikingly, at protein aggregates themselves. Degraders capable of clearing α-synuclein and tau aggregates simultaneously represent a conceptual breakthrough for neurodegeneration, because both misfolded proteins cross-seed one another and together drive pathology in diseases such as dementia with Lewy bodies and Alzheimer’s. The authors note that these designs repurposed aggregation-binding scaffolds, such as thioflavin-derived amyloid ligands, as warheads, demonstrating that even supramolecular pathological assemblies can be brought into the reach of the ubiquitin-proteasome system. In parallel, dual GSPT1/BRD4 degraders exploit cereblon-mediated translational termination factor degradation alongside epigenetic transcriptional collapse to kill leukemia cells through mechanistically independent routes.

The translational horizon is coming into view. The first PROTAC, vepdegestrant, has moved targeted degradation into approved oncology practice, and clinically advanced single-target degraders have validated the modality’s core principles. Dual degraders now face the harder test of converting dual potency into dual efficacy with an acceptable safety profile. The review identifies pharmacokinetics as the chief obstacle: dual PROTACs are large, often exceeding the classic rule-of-five boundaries for oral absorption, and their high polarity and molecular weight challenge permeability, metabolic stability, and brain penetration. Off-target toxicity arising from polypharmacology is a second concern, since the same warhead promiscuity that enables dual engagement can degrade unintended proteins. Strategies such as introducing one-carbon bridges to lower lipophilicity, incorporating molecular glue features into PROTAC scaffolds, and exploiting CD36-mediated endocytosis to improve cellular uptake are among the emerging countermeasures surveyed.

What the review ultimately delivers is a map. By consolidating the 2023 to 2026 literature into a coherent framework of homologous versus cross-pathway dual targets, and by extracting transferable SAR lessons on warhead choice, linker optimization, and E3 ligase pairing, the authors have given medicinal chemists a practical playbook for the next round of design. If the remaining pharmacokinetic and selectivity problems can be tamed, dual PROTACs could compress combination therapy into a single pill, offering patients with complex, drug-resistant diseases a weapon that dismantles two pillars of pathology at once. For a field that has already taught medicine to delete proteins rather than merely inhibit them, degrading disease networks two nodes at a time may be the logical, and inevitable, next act.

Subject of Research: Development of dual PROTACs that simultaneously degrade two disease-related proteins for therapeutic applications in cancer and neurodegenerative disease.

Article Title: Recent advances of dual PROTACs for potential therapeutic applications

Article References: Li, S.-R., Yu, M.-Q., Du, B.-Q., Jin, K.-J., Chen, S.-X., Hui, Z., Zhang, H., Mao, N.-D., Gao, Y., & Ye, X.-Y. (2026). Recent advances of dual PROTACs for potential therapeutic applications. Molecular Diversity. https://doi.org/10.1007/s11030-026-11734-9

Image Credits: AI Generated

DOI: 10.1007/s11030-026-11734-9

Keywords: PROTACs, targeted protein degradation, dual degraders, ubiquitin-proteasome system, E3 ubiquitin ligase, cancer therapy, neurodegenerative disease, BCL-2, BRD4, CDK inhibitors, structure-activity relationships, drug discovery

Neuroblastoma represents one of the most common solid tumors in infancy and early childhood, often characterized by its ability to evade differentiation signals and adopt a highly malignant, proliferative state. Conventional therapies, including chemotherapy, surgery, and radiation, have limited efficacy, particularly in high-risk cases. Retinoic acid (RA), a derivative of vitamin A, has been used as a differentiation-inducing agent, aiming to redirect malignant neuroblastoma cells toward a more mature, less aggressive phenotype. However, resistance to RA is a significant obstacle, curbing its therapeutic utility in many patients.

The study in question centers on the critical role of CDKs, a family of serine/threonine kinases that orchestrate cell cycle progression and influence cellular differentiation. Overactivity of specific CDK isoforms has been linked to uncontrolled proliferation in various cancers. By targeting CDKs with small-molecule inhibitors, the researchers aimed to disrupt this pathological cell cycle regulation, inducing a differentiation program within neuroblastoma cells. The team’s innovative approach rested on the premise that CDK inhibition might normalize aberrant cell cycle signals, thereby restoring the cells’ intrinsic ability to mature upon RA exposure.

Employing a suite of in vitro experiments, the authors first demonstrated that treatment with selective CDK inhibitors led to marked morphological changes in neuroblastoma cell lines, indicative of differentiation. Cells exhibited neurite outgrowth and altered expression of differentiation-associated markers, signaling a shift away from the undifferentiated, proliferative phenotype. Quantitative analyses further confirmed these phenotypic changes, reinforcing the hypothesis that CDK activity plays a pivotal role in maintaining the malignant state.

Beyond morphological evidence, the molecular fingerprint of gene expression changes under CDK inhibition was carefully dissected. Transcriptomic profiling revealed upregulation of neuronal differentiation genes, accompanied by downregulation of proliferation-associated transcripts. This transcriptional reprogramming highlights the multifaceted impact of CDK inhibitors and suggests that they orchestrate complex cascades to tip the balance from cell division toward maturation. The findings illuminate previously underappreciated connections between cell cycle regulators and differentiation pathways in neuroblastoma.

Crucially, the study explored the synergistic potential of combining CDK inhibitors with retinoic acid treatment. While RA monotherapy induces differentiation in susceptible cells, the addition of CDK inhibitors significantly amplified this effect, sensitizing resistant cell populations to RA’s differentiating influence. This combinatorial strategy was tested across multiple neuroblastoma cell lines, illustrating broad applicability and robustness of the therapeutic benefit. Enhanced induction of differentiation markers and greater reduction in cell viability underscored the synergistic interaction.

Mechanistically, the combination appeared to converge on shared signaling networks, including modulation of retinoic acid receptor activity and downstream effectors. CDK inhibitors seem to prime the chromatin landscape and transcriptional machinery, heightening cellular responsiveness to RA. This facilitates a more profound reprogramming of gene expression, effectively overcoming barriers that limit RA efficacy when used alone. These insights provide a mechanistic rationale to propel clinical investigation of combination therapies.

Furthermore, the research delineates how inhibition of specific CDK isoforms impacts neuroblastoma pathology. The data emphasize the nuanced roles of individual CDKs beyond canonical cell cycle progression. By dissecting these roles, the study paves the way for precision-medicine approaches where tailored inhibitors targeting distinct CDKs could be selected based on tumor genotype and phenotype. Such customization holds promise for maximizing therapeutic impact while minimizing adverse effects.

In addition to detailed cellular and molecular analyses, the authors also evaluated functional consequences of the therapeutic interventions. Differentiated neuroblastoma cells displayed decreased clonogenic potential and diminished capacity for anchorage-independent growth, hallmark features of tumorigenicity. These findings underscore that the induced differentiation correlates with loss of malignant characteristics, crucial for translating laboratory observations into effective clinical strategies.

The implications of this study extend beyond neuroblastoma, suggesting that CDK inhibitors might prove beneficial in other cancers where differentiation blockade contributes to malignancy. The idea of combining cell cycle modulators with differentiation agents represents an elegant and rational therapeutic paradigm. Importantly, the existing clinical use of RA and CDK inhibitors facilitates potential rapid translation into clinical trials, accelerating the timeline from bench to bedside.

Despite the promise, the authors caution that further investigations are requisite to address outstanding questions. These include the long-term stability of induced differentiation, potential resistance mechanisms to combined therapy, and optimal dosing regimens to maximize efficacy while curtailing toxicity. Animal model studies and eventual clinical trials will be instrumental in validating the efficacy and safety observed in cellular models.

The study also touches on the broader biological significance of CDKs in developmental contexts and cancer. By revealing how CDK activity intersects with differentiation pathways in neuroblastoma, the work underscores fundamental principles of cell biology and oncogenic transformation. Such knowledge deepens our understanding of tumor biology and identifies vulnerabilities amenable to therapeutic exploitation.

In conclusion, the research by Shokraie and colleagues marks a pivotal advance in neuroblastoma treatment strategies. Through meticulous dissection of molecular mechanisms and therapeutic synergy, the study provides a robust foundation for developing combination treatments that harness the power of CDK inhibitors and retinoic acid. This dual attack on cell proliferation and differentiation blockade offers renewed hope for improving outcomes in pediatric neuroblastoma patients facing limited therapeutic options.

As this research progresses toward clinical application, it exemplifies the critical importance of integrating molecular insights with translational goals. Harnessing the interplay between cell cycle regulation and differentiation not only expands the therapeutic arsenal but also exemplifies innovation in combating childhood cancer. The dynamic nature of neuroblastoma biology and the urgent need for more effective therapies make this combined CDK inhibitor and RA strategy a beacon for future oncology research and treatment.

Subject of Research: Neuroblastoma, CDK inhibition, cellular differentiation, retinoic acid sensitivity, pediatric oncology

Article Title: CDK inhibitors promote neuroblastoma cell differentiation and increase sensitivity to retinoic acid—a promising combination strategy for therapeutic intervention

Article References:
Shokraie, F., Lechermeier, L., Bordihn, P. et al. CDK inhibitors promote neuroblastoma cell differentiation and increase sensitivity to retinoic acid—a promising combination strategy for therapeutic intervention. Cell Death Discov. 11, 363 (2025). https://doi.org/10.1038/s41420-025-02637-z

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02637-z