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

Enter PROTAC (Proteolysis Targeting Chimera) technology, a transformative approach that diverges fundamentally from traditional inhibition by harnessing the cell’s own ubiquitin-proteasome system to selectively degrade the LSD1 enzyme. PROTAC molecules operate catalytically, tethering the target protein to an E3 ubiquitin ligase which flags it for destruction. This elegant mechanism ensures profound and durable depletion of LSD1 at lower compound concentrations compared to occupancy-driven inhibitors. Such catalytic degradation promises not only heightened efficacy but also reduced emergence of drug resistance and diminished off-target toxicities, positioning PROTACs as a next-generation therapeutic platform in oncology.

In this groundbreaking study, the research team engineered a series of PROTAC compounds by fusing an LSD1-binding moiety named LI-1 with the cereblon (CRBN)-recruiting ligand thalidomide via linkers of varying lengths. Through meticulous structure-activity relationship (SAR) investigations, a candidate designated LD-110 surfaced as the most potent and selective degrader of LSD1. Biochemical assays revealed that LD-110 substantially diminished LSD1 protein levels in breast and lung cancer cell lines in both a time-dependent and dose-dependent fashion. Notably, the half-maximal degradation concentrations (DC₅₀) of LD-110 were impressively low in MDA-MB-231 and MDA-MB-453 breast cancer cells, registering at 9.54 and 7.08 nanomolar, respectively. Although lung cancer H520 cells exhibited a higher DC₅₀ of 446 nanomolar, this still represents significant efficacy given the challenge of targeting non-hematological tumors.

Validation of the underlying degradation mechanism was achieved through rigorous control experiments. The authors demonstrated that the proteasome inhibitor MG132 and the neddylation inhibitor MLN4924 effectively abrogated LD-110-induced LSD1 degradation, confirming the critical involvement of the ubiquitin-proteasome system and the CRBN E3 ligase pathway. Furthermore, competitive inhibition with the LI-1 warhead and thalidomide ligand prevented degradation, and a methylated analog of LD-110 (LD-110Me), incapable of binding CRBN, failed to induce either LSD1 degradation or downstream substrate accumulation. These findings collectively solidify that LD-110 functions as a bona fide PROTAC, exploiting CRBN recruitment to catalyze targeted proteostasis.

Beyond biochemical validation, the anti-proliferative effects of LD-110 were striking. The compound exhibited potent growth inhibition across diverse cancer cell lines, yielding half-maximal inhibitory concentrations (IC₅₀) ranging broadly but often in the sub-micromolar range. Of equal importance, pharmacokinetic profiling demonstrated that LD-110 possesses favorable in vivo characteristics, including bioavailability and metabolic stability, which translated into marked tumor growth suppression in both breast and lung cancer xenograft models. Remarkably, this potent anti-tumor activity was achieved without detectable systemic toxicity, suggesting an attractive therapeutic window for further development.

Delving into the mechanistic underpinnings of LD-110’s cytotoxicity revealed a sophisticated orchestration of cellular stress pathways. LD-110 was found to induce apoptotic cell death primarily via triggering endoplasmic reticulum (ER) stress, converging on activation of the ATF4-CHOP axis—a central regulator of stress-induced apoptosis. On one hand, transcriptional modulation stems from LSD1 degradation leading to increased H3K4 dimethylation (H3K4me2), which facilitates ATF4 gene expression. On the other hand, LD-110 also stimulates reactive oxygen species (ROS) production resulting in DNA damage, which activates the GCN2-eIF2α pathway to augment translational synthesis of ATF4 protein. This dual mechanism synergistically amplifies ATF4 levels, engaging downstream apoptotic effectors.

The ATF4-CHOP pathway modulates critical determinants of cell fate by rebalancing members of the BCL-2 protein family. Specifically, LD-110 elevates the expression of NOXA, a potent pro-apoptotic factor, while concomitantly reducing MCL1, an anti-apoptotic protein that often confers resistance to cell death. This shift in protein equilibrium decisively steers cancer cells toward programmed apoptosis, underpinning the robust anticancer effects observed.

Nonetheless, the use of CRBN as the E3 ligase recruitment element inherently carries limitations related to off-target degradation. CRBN naturally targets substrates such as GSPT1 and the IKZF family, which are not the intended therapeutic targets. Consistent with this, LD-110 also promoted degradation of GSPT1 alongside LSD1. Intriguingly, the researchers discovered that GSPT1 competes with LSD1 for LD-110 binding, thereby diminishing the degrader’s efficiency toward LSD1. Through siRNA-mediated knockdown of GSPT1, the inhibitory effect on LSD1 degradation was alleviated, resulting in enhanced LD-110 potency and more pronounced growth inhibition of cancer cells.

This observation suggests a compelling therapeutic strategy: combining LD-110 with a selective GSPT1 degrader could yield synergistic anti-tumor activity through dual pathway engagement. Such a combination may allow for dose reduction, potentially minimizing toxicity while maximizing efficacy—an elegant example of precision polypharmacology.

In summation, this investigation heralds LD-110 as a pioneering PROTAC molecule that effectively depletes LSD1, exhibiting significant anticancer activity in vitro and in vivo. The dual mechanism of inducing ER stress and modulating epigenetic marks represents a novel therapeutic angle to combat cancers characterized by LSD1 overexpression. With favorable pharmacokinetic and safety profiles, LD-110 stands poised as a promising candidate to advance into clinical development, potentially transforming the therapeutic landscape for patients afflicted with breast, lung, and possibly other cancers.

As the field of targeted protein degradation continues to revolutionize drug discovery, studies such as this provide compelling proof-of-concept that PROTACs can surpass the limitations of traditional inhibitors. By capitalizing on polyfunctional molecular design, researchers are opening avenues toward durable, selective, and potent cancer therapies that exploit intrinsic cellular machinery to disarm oncogenic drivers.

Future research will undoubtedly explore further optimization of linker chemistry, E3 ligase selection, and combination regimens with other targeted agents. Moreover, deciphering and mitigating off-target effects inherent to PROTAC technology remains a priority to maximize clinical benefit. The promising results reported here pave the way for a new era in epigenetic cancer therapy, leveraging protein degradation machinery to deliver precise, potent, and lasting tumor suppression.

Subject of Research: LSD1 Protein Degradation Using PROTAC Technology for Cancer Therapy

Article Title: Discovery of LD-110 as a Potent PROTAC Degrader of LSD1 with Therapeutic Efficacy in Breast and Lung Cancer Models

Web References:
10.1016/j.scib.2025.10.024

Keywords:
Life sciences, Health and medicine, Biochemistry, Cancer treatments