TAC Attack!: The Extended Universe of Targeted Protein Degraders

Targeted protein degradation (TPD) has emerged as a key strategy for the development of small-molecule therapeutics, leveraging clever chemistries to induce the specific degradation of protein targets. Early molecular glues relied on the serendipitous discovery of molecules capable of modulating the stability of protein-protein interactions (PPIs).  In 2001, the initial report of Proteolysis-Targeting Chimeras (PROTACs) introduced a transformative framework:   heterobifunctional molecules designed such that a moiety binding a protein target is connected via flexible linker to an E3 ligase-recruiting domain. By bringing an E3 ligase into proximity of the target protein, these compounds are able to selectively induce target ubiquitination and subsequent proteasomal degradation.

The proven power of these TPD modalities has spurred significant interest in recent decades – both in molecular glues and PROTACs themselves and in variant strategies that further expand the therapeutic toolbox. Here, we’ll take a tour through a range of emerging TPD modalities that leverage the principles underlying targeted degradation in unique, innovative, and effective ways.

Modalities Leveraging Proteasomal Degradation

SNIPER: Specific and Non-genetic IAP-dependent Protein Eraser

SNIPERs are similar to PROTACs in that they recruit E3 ligases to a target protein to effect proteasomal degradation. While PROTACs typically leverage the E3 ligases CHL and CBLN, SNIPERs specifically recruit inhibitor of apoptosis proteins (IAPs) for target ubiquitination. In addition to providing alternative machinery for targeted proteasomal degradation, SNIPERs have the advantage of triggering IAP degradation alongside target degradation; because IAPs are commonly overexpressed in cancer, their reduction can increase therapeutic efficacy. SNIPER technology has been applied for the degradation of a broad range of protein targets, primarily for the treatment of cancer.

Nano-PROTAC: Nanoscale Proteolysis-Targeting Chimera

Nano-PROTAC technology enhances the deliverability of traditional PROTACs through the incorporation of a functionalized nanocarrier, such as a lipid-based nanoparticle, inorganic nanoparticle, or nucleic acid aptamer. In addition to overcoming drug-delivery challenges, this approach enables the targeted delivery of PROTACs to specific tissues or cell types, and researchers have further proposed the use of nanosystems to enable temporal control of drug release in response to temperature, light, or magnetic fields.  One recent report described the use of an in vivo self-assembled nano-PROTAC capable of simultaneously degrading AR and HSP90 to treat cases of castration-resistant prostate cancer that have acquired drug resistance.

Modalities Leveraging Lysosomal Degradation

AUTAC: Autophagy-Targeting Chimera

AUTACs, first described in 2019, were developed to address limitations in the scope of PROTAC-degradable targets; because PROTAC technology relies on the proteasomal degradation system, it is not effective at clearing large protein aggregates or organelles (such as mitochondria). AUTACs remedy this problem by linking a target-binding ligand to a guanine derivative, rather than to an E3 ligase recruiter. This approach results in the recruitment of the autophagy machinery, a cellular degradation system that involves the formation of target-containing autophagosomes that fuse with hydrolase-filled lysosomes. AUTACs have been successfully applied for the targeted degradation of Mcl1 for the treatment of multiple myeloma and of Tau oligomers for the treatment of Alzheimer’s disease.

ATTEC: Autophagosome-Tethering Compound

ATTECs, initially reported in 2019, also route target proteins to the autophagy-lysosome system for degradation. RBather than triggering degradation by a guanine derivative (as in AUTACs), ATTACs leverage LC3, a protein involved in autophagosome formation. By linking a target-binding moiety to an LC3 ligand, researchers can induce target degradation. This technology was originally described for the degradation of mutant huntingtin protein (mHTT) in the treatment of Huntington’s disease and has since been applied to induce degradation of CDK9, PDEδ, and lipid droplets (LDs).

LYTAC: Lysosome-Targeting Chimera

Another class of targeted autophagy inducers – LYTACs – were first described in 2020. Their development was prompted by the desire to apply a PROTAC-like strategy for the degradation of extracellular and membrane-associated proteins. To accomplish this, LYTACs fuse a target-binding element (which can be a small molecule, an antibody, or a peptide) to a glycopeptide ligand binding the CI-M6PR receptor. Once the target is co-localized with CI-M6PR, the receptor shuttles targeted cargo to a prelysosomal compartment before its eventual lysosomal degradation. Further variations on this technology have enabled cell type-specific degradation, as well as the incorporation of gene silencing capabilities.

AbTAC: Antibody-Based PROTAC

AbTACs, originally described in 2021, recruit membrane-bound E3 ligases to target cell-surface proteins for lysosomal degradation. Rather that joining two small-molecule ligands via a flexible linker, an AbTAC consists of a recombinant bispecific IgG antibody recognizing both the target protein and a transmembrane E3 ligase (such as RNF43). Binding of both components induces target internalization and subsequent lysosomal degradation. Subsequent research efforts have further optimized this approach and demonstrated its efficacy in degrading the clinically relevant membrane targets PD-L1 and EGFR.

kineTAC: Cytokine Receptor-Targeting Chimeras

Another lysosomal-based degradation strategy – kineTAC – is similar to the AbTAC approach in that it relies on a bispecific antibody with one target-binding arm and a second degradation-facilitating arm. In the case of kineTACs, the latter arm is specifically a cytokine, enabling it to bind to its appropriate cytokine receptor. This binding triggers cytokine-mediated internalization of the kineTAC complex, ultimately leading to lysosomal degradation of this target. Following the initial description of this technology, subsequent research efforts synthesized a panel of 81 kineTAC molecules that can be leveraged for the targeted degradation of cell-surface or extracellular targets.

AUTOTAC: Autophagy-Targeting Chimera

First reported in 2022, AUTOTACs are similar to the modalities described above in that they employ the autophagy-lysosome system to enact target degradation. AUTOTACs, however, accomplish this recruitment through a unique mechanism. Namely, AUTOTACs include a ligand for the ZZ domain of p62. Following target binding, the AUTOTAC recruits p62, which subsequently self-oligomerizes before complexes are degraded through autophagy. The AUTOTAC strategy has been recently applied for the degradation of pathologic tau aggregates.

Modalities Leveraging Alternative Degradation Pathways

RiboTAC: Ribonuclease-Targeting Chimera

Rather than inducing the degradation of a targeted protein, RiboTACs leverage endogenous ribonucleases (such as RNase L) to specifically degrade target RNA species. This approach seeks to ablate a target at the RNA level, either prior to translation (in the case of mRNAs) or as a strategy to degrade non-coding RNAs with functional effects. In comparison to ASOs, RiboTACs can offer increased specificity and potency, but further research is required before their clinical use can be validated. To date, RiboTACs have been developed to target miRNAs, mRNAs, and viral RNAs. One recently reported variation on this technology is the tumor microenvironment activated RiboTAC, or TaRiboTAC, which incorporates a cage that is specifically removed once the molecule encounters tumor-like environmental conditions.

BacPROTAC: Bacterial PROTAC

BacPROTACs are distinct from the other modalities highlighted herein, as they are intended to degrade target proteins within bacterial (rather than eukaryotic) cells. As such, they leverage the bacterial protease ClpC:ClpP, using a bifunctional molecule to recruit target proteins to this machinery. In addition to their use as research tools, BacPROTACs have significant potential as antibiotic treatments. Indeed, recent research has demonstrated their antimycobacterial activity, including against drug-resistant mycobacteria.

 

Interested in exploring any of these therapeutic modalities? Momentum Biotechnologies offers a broad range of CRO services to support drug discovery and development, including for emerging technologies like those described in this post. From target identification to hit discovery to pre-clinical proteomics, our mass spec-driven workflows provide researchers with the data they need to drive their programs forward. If you’re ready to learn more about how these services can accelerate your research efforts, click here to connect with our scientific team. 

 

Sources

Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR & Bertozzi CR. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol 17, 937-946 (2021).

Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM & Bertozzi CR. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291-297 (2020).

Bao J, Chen Z, Li Y, Chen L, Wang W, Sheng C & Dong G. Discovery of Novel PDEδ Autophagic Degraders: A Case Study of Autophagy-Tethering Compound (ATTEC). ACS Med Chem Lett 15, 29-35 (2023).

Brown DA, Davies JJ, Fecht S, Zhang Y, Kunzelmann S , Kent L, Skehel M & Morreale FE. BacPROTACs outperform inhibitors in Mycobacterium tuberculosis. bioRxiv (2026).

Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB & Wells JA. Development of Antibody-Based PROTACs for the Degradation of Cell-Surface Immune Checkpoint Protein PD-L1. J Am Chem Soc 143, 593-598 (2021).

Darling S, Bajrami I & West SC. From serendipity to strategy: molecular glue degraders in cancer therapeutics. Crit Rev Biochem Mol Biol 60, 200-230 (2025).

Ding Y, Xing D, Fei Y, Luo S & Lu B. Perspectives of autophagy-tethering compounds (ATTECs) in drug discovery. Med Plus 1, 100004 (2024).

Elshazly AM, Hosseini N, Vangala J, Shen S, Neely V, Hu X, Pagare PP, Harada H, Grant S & Radhakrishnan SK. Proteasome inhibition enhances lysosome-mediated targeted protein degradation. Cell Death Dis 17, 614 (2026).

Fu Y, Chen N, Wang Z, Luo S, Ding Y & Lu B. Degradation of lipid droplets by chimeric autophagy-tethering compounds.Cell Res 31, 965-979 (2021).

Gramespacher JA, Cotton AD, Burroughs PWW, Seiple IB & Wells JA. Roadmap for Optimizing and Broadening Antibody-Based PROTACs for Degradation of Cell Surface Proteins. ACS Chem Biol 17, 1259-1268 (2022).

Huang Y, Zhou X, Zhang Y, Xie M, Wang F, Qin J, Ye H, Zhang H, Zhang C & Hong J. A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation. Adv Sci (Weinh) 11, 2306248 (2024).

Ji CH, Kim HY, Lee MJ, Heo AJ, Park DY, Lim S, Shin S, Ganipisetti S, Yang WS, Jung CA, Kim KY, Jeong EH, Park SH, Kim SB, Lee SJ, Na JE, Kang JI, Chi HM, Kim HT, Kim YK, Kim BY & Kwon YT. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat Comm 13, 904 (2022).

Junk L, Schmiedel VM, Guha S, Fischel K, Greb P, Vill K, Krisilia V, van Geelen L, Rumpel K, Kaur P, Krishnamurthy RV, Narayanan S, Shandil RK, Singh M, Kofink C, Mantoulidis A, Biber P, Gmaschitz G, Kazmaier U, Meinhart A, Leodolter J, Hoi D, Junker S, Morreale FE, Clausen T, Kalscheuer R, Weinstabl H, Boehmelt G. Homo-BacPROTAC-induced degradation of ClpC2 as a strategy against drug-resistant mycobacteria. Nat Commun 15, 2005 (2024).

Junker S & Clausen T. BacPROTAC-induced degradation as a new antibiotic concepts. Trends Biochem Sci 51, 249-260 (2026).

Komachankandy S & Lee Y. Targeted RNA Degradation as a Promising Therapeutic Strategy. Int J Mol Sci 26, 10767 (2025).

Kumru K, Yao Z, Holmes BB, Zhao F, Zhang Y, Ferrara E, Peters-Clarke TM, Leung KK & Wells JA. A cytokine receptor-targeting chimera toolbox for expanding extracellular targeted protein degradation. Proc Natl Acad Sci U S A 123, e2524129123 (2026).

Lee J, Kim SB, Kim HY, Lee GE, Lee DW, Jung EH, Lee JS, Cho EH, Park H-B, Park D, Kwon SC, Noh JE, Cha HS, Oh HJ, Lee SH, Šterbenc N, Choi CY, Lee MJ, Chi HM, Suh YH, Lee KJ, Han DH, Sung KW, Pavlin D, Kim ST, Ji CH, Pipan MZ & Kwon YT. Targeted degradation of pathologic tau aggregates via AUTOTAC ameliorates tauopathy. bioRxiv (2025).

Li Z, Wang C, Wang Z, Zhu C, Li J, Sha T, Ma L, Gao C, Yang Y, Sun Y, Wang J, Sun X, Lu C, Difiglia M, Mei Y, Ding C, Luo S, Dang Y, Ding Y, Fei Y & Lu B. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds.Nature 575, 203-209 (2019).

Morreale FE, Kleine S, Leodolter J, Junker S, Hoi DM, Ovchinnikov S, Okun A, Kley J, Kurzbauer R, Junk L, Guha S, Podlesainski D, Kazmaier U, Boehmelt G, Weinstabl H, Rumpel K, Schmiedel VM, Hartl M, Haselbach D, Meinhart A, Kaiser M & Clausen T. BacPROTACs mediate targeted protein degradation in bacteria. Cell 185, 2338-2353 (2022).

Naito M, Ohoka N & Shibata N. SNIPERs—Hijacking IAP activity to induce protein degradation. Drug Disc Today Technol 31, 35-42 (2019).

Niebel B, Chen W, Mukai K & Henry C. LYTACs and other extracellular targeted protein degradation TACnologies: guiding principles and potential clinical prospects. Drug Discov Today 31, 104601 (2026).

Ohoka N, Okuhira K, Ito M, Nagai K, Shibata N, Hattori T, Ujikawa O, Shimokawa K, Sano I, Koyama R, Fujita H, Teratani M, Matsumoto H, Imaeda Y, Nara H, Cho N & Naito M. In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERS). J Bio Chem 292, 4556-4570 (2017).

Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano J-AC, Cotton AD, Steri V & Wells JA. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat Biotechnol 41, 273-281 (2023).

Rusciano D, Gagliano C, Avitabile A & Maya-Vetencourt JF. Targeted RNA Degradation by RIBOTACs: A Novel Therapeutic Avenue for Ophthalmic Diseases. Int J Mol Sci 27, 1493 (2026).

Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM & Deshaies RJ. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A 98, 8554-8559 (2001).

Song Y, Dong Q-Q, Ni Y-K, Xu X-L, Chen C-X & Chen W. Nano-Proteolysis Targeting Chimeras (Nano-PROTACs) in Cancer Therapy. Int J Nanomed 19, 5739-5761 (2024).

Takahashi D, Moriyama J, Nakamura T, Miki E, Takahashi E, Sato A, Akaike T, Itto-Nakama K & Arimoto H. AUTACs: Cargo-Specific Degraders Using Selective Autophagy. Mol Cell 76, 797-810 (2019).

Wang C, Zhang Y, Shi L, Yang S, Chang J, Zhong Y, Li Q & Xing D. Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents. J Enzyme Inhib Med Chem 37, 1437-1453 (2022).

Wu X, Shu Y, Zheng Y, Zhang P, Cong H, Zou Y, Cai H & Zha Z. Recent Advances in Nanomedicine: Cutting-Edge Research on Nano-PROTAC Delivery Systems for Cancer Therapy. Pharmaceutics 17, 1037 (2025).

Yang, F-Y, Zhang N-Y, Yang Y, Chen D, Wu L-Y, Wang W-K, Wang H-X, Wen Z, Cai M-Z, Li H-Z, Huang H, An H-W, Wang H & Xing N-Z. In vivo self-assembled nano-PROTAC for the dual degradation of AR and HSP90 to overcome castration-resistant prostate cancer resistance. Sig Transduct & Targ Ther 10, 346 (2025).

Yang X, Wang D, Li C, Zhang Y, Yang J, Liu M, Xing D, Jiang W, Xu S & Wang C. Nano-PROTACs for precision medicine: engineering strategies for enhanced targeting and potency. J Nanobiotechnology 24, 120 (2026).

Yoon BH, Kim J, Sengupta S, Park C-J, Ko M, Kang JH, Ko YT, Kim Y, Lim SM, Bae Y, Choi M, Jang Y, Kwon HJ, Son HJ, Kim HJ, Sim T, Chang K-A & Lee M-S. Targeted autophagic clearance of Tau protects against Alzheimer’s disease through amelioration of Tau-mediated lysosomal stress. Theranostics 15, 9240-9260 (2025).

Zeng Y, Xiao J, Xu Y, Wei F, Tian L, Gao Y, Chen Y & Hu Y. Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs. J Med Chem 66, 12877-12893 (2023).

Zhang Y, Zhu J, Qiu L, Lv Z, Zhao Z, Ren X, Guo Y, Chen Y, Li M, Fan Y, Han Z, Feng Y & Shi H. Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy. Nat Commun 16, 1288 (2025).

Zhao L, Zhao J, Zhong K, Tong A & Jia D. Targeted protein degradation: mechanisms, strategies and application. Sig Transduc Targ Ther 7, 113 (2022).